Editorial

5 pages, 205 KiB

Open AccessEditorial

by Hassan Bousbaa

Pharmaceutics 2023, 15(2), 605; https://doi.org/10.3390/pharmaceutics15020605 - 10 Feb 2023

Viewed by 1203

Owing to the exceptional complexity of the development and progression of cancer, diverse cancer types are alarmingly increasing worldwide [...] Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

Research

Jump to: Editorial, Review

18 pages, 7621 KiB

Open AccessArticle

PD-1 Cellular Nanovesicles Carrying Gemcitabine to Inhibit the Proliferation of Triple Negative Breast Cancer Cell

by Hualian Zha, Zhanxue Xu, Xichao Xu, Xingyu Lu, Peilin Shi, Youmei Xiao, Hsiang-I Tsai, Dandan Su, Fang Cheng, Xiaoli Cheng and Hongbo Chen

Pharmaceutics 2022, 14(6), 1263; https://doi.org/10.3390/pharmaceutics14061263 - 14 Jun 2022

Cited by 4 | Viewed by 2427

Abstract

PD-1 inhibitor Keytruda combined with chemotherapy for Triple-negative breast cancer (TNBC) has been approved for FDA, successfully representing the combination therapy of immunotherapy and chemotherapy for the first time in 2020. However, PD-L1 inhibitor Tecentriq combined with albumin paclitaxel using the similar strategy [...] Read more.

PD-1 inhibitor Keytruda combined with chemotherapy for Triple-negative breast cancer (TNBC) has been approved for FDA, successfully representing the combination therapy of immunotherapy and chemotherapy for the first time in 2020. However, PD-L1 inhibitor Tecentriq combined with albumin paclitaxel using the similar strategy failed to achieve the expected effect. Therefore, it is still necessary to explore new effective immunotherapy and chemotherapy-based combined strategies. We developed a cell membrane-derived programmed death-ligand 1(PD-1) nanovesicle to encapsulate low-dose gemcitabine (PD-1&GEM NVs) to study the effect on breast cancer in vitro and in vivo. We found that engineered PD-1&GEM NVs could synergistically inhibit the proliferation of triple-negative breast cancer, which interacted with PD-L1 in triple-negative breast cancer to disrupt the PD-L1/PD-1 immune inhibitory axis and promoted cancer cell apoptosis. Moreover, PD-1&GEM NVs had better tumor targeting ability for PD-L1 highly-expressed TNBC cells, contributing to increasing the drug effectiveness and reducing toxicity. Importantly, gemcitabine-encapsulated PD-1 NVs exerted stronger effects on promoting apoptosis of tumor cells, increasing infiltrated CD8⁺ T cell activation, delaying the tumor growth and prolonging the survival of tumor-bearing mice than PD-1 NVs or gemcitabine alone. Thus, our study highlighted the power of combined low-dose gemcitabine and PD-1 in the nanovesicles as treatment to treat triple-negative breast cancer. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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17 pages, 3311 KiB

Open AccessArticle

Navitoclax Enhances the Therapeutic Effects of PLK1 Targeting on Lung Cancer Cells in 2D and 3D Culture Systems

by Bárbara Pinto, Pedro Novais, Ana C. Henriques, Juliana Carvalho-Tavares, Patrícia M. A. Silva and Hassan Bousbaa

Pharmaceutics 2022, 14(6), 1209; https://doi.org/10.3390/pharmaceutics14061209 - 06 Jun 2022

Cited by 3 | Viewed by 2028

Abstract

The efficacy of antimitotics is limited by slippage, whereby treated cells arrested in mitosis exit mitosis without cell division and, eventually, escape apoptosis, constituting a serious resistance mechanism to antimitotics. Strategies to overcome slippage should potentiate the cancer cell killing activity of these [...] Read more.

The efficacy of antimitotics is limited by slippage, whereby treated cells arrested in mitosis exit mitosis without cell division and, eventually, escape apoptosis, constituting a serious resistance mechanism to antimitotics. Strategies to overcome slippage should potentiate the cancer cell killing activity of these antimitotics. Such strategies should accelerate cell death in mitosis before slippage. Here, we undertook a mechanistic analysis to test whether the apoptosis activator Navitoclax potentiates apoptosis triggered by the antimitotic BI2536, a potent inhibitor of Polo-like kinase 1 (PLK1) with the goal of overcoming slippage. We found that cancer cells in 2D cultures treated with BI2536 alone accumulate in mitosis, but a significant fraction of arrested cells undergo slippage and survive. Remarkably, combining BI2536 with Navitoclax dramatically reduces slippage, shifting the cell fate to accelerated death in mitosis. The results are confirmed in 3D spheroids, a preclinical system that mimics in vivo tumor drug responses. Importantly, in 3D spheroids, the effect of the BI2536/Navitoclax combination requires a lower therapeutic dosage of each drug, underlying its potential to improve the therapeutic index. Our results highlight the relevance of apoptosis potentiators to circumvent slippage associated with antimitotics. The combination of BI2536 with Navitoclax shows in vitro synergy/additive effect, which warrants further clinical research. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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11 pages, 3537 KiB

Open AccessArticle

HPMA Copolymer Mebendazole Conjugate Allows Systemic Administration and Possesses Antitumour Activity In Vivo

by Martin Studenovský, Anna Rumlerová, Jiřina Kovářová, Barbora Dvořáková, Ladislav Sivák, Libor Kostka, Daniel Berdár, Tomáš Etrych and Marek Kovář

Pharmaceutics 2022, 14(6), 1201; https://doi.org/10.3390/pharmaceutics14061201 - 04 Jun 2022

Cited by 2 | Viewed by 2038

Abstract

Mebendazole and other benzimidazole antihelmintics, such as albendazole, fenbendazole, or flubendazole, have been shown to possess antitumour activity, primarily due to their microtubule-disrupting activity. However, the extremely poor water-solubility of mebendazole and other benzimidazoles, resulting in very low bioavailability, is a serious drawback [...] Read more.

Mebendazole and other benzimidazole antihelmintics, such as albendazole, fenbendazole, or flubendazole, have been shown to possess antitumour activity, primarily due to their microtubule-disrupting activity. However, the extremely poor water-solubility of mebendazole and other benzimidazoles, resulting in very low bioavailability, is a serious drawback of this class of drugs. Thus, the investigation of their antitumour potential has been limited so far to administering repeated high doses given peroral (p.o.) or to using formulations, such as liposomes. Herein, we report a fully biocompatible, water-soluble, HPMA copolymer-based conjugate bearing mebendazole (P-MBZ; M_w 28–33 kDa) covalently attached through a biodegradable bond, enabling systemic administration. Such an approach not only dramatically improves mebendazole solubility but also significantly prolongs the half-life and ensures tumour accumulation via an enhanced permeation and retention (EPR) effect in vivo. This P-MBZ has remarkable cytostatic and cytotoxic activities in EL-4 T-cell lymphoma, LL2 lung carcinoma, and CT-26 colon carcinoma mouse cell lines in vitro, with corresponding IC₅₀ values of 1.07, 1.51, and 0.814 µM, respectively. P-MBZ also demonstrated considerable antitumour activity in EL-4 tumour-bearing mice when administered intraperitoneal (i.p.), either as a single dose or using 3 intermittent doses. The combination of P-MBZ with immunotherapy based on complexes of IL-2 and anti-IL-2 mAb S4B6, potently stimulating activated and memory CD8⁺ T cells, as well as NK cells, further improved the therapeutic effect. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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12 pages, 1681 KiB

Open AccessArticle

Evaluation of 3-Borono-l-Phenylalanine as a Water-Soluble Boron Neutron Capture Therapy Agent

by Naoya Kondo, Fuko Hirano and Takashi Temma

Pharmaceutics 2022, 14(5), 1106; https://doi.org/10.3390/pharmaceutics14051106 - 22 May 2022

Cited by 13 | Viewed by 3525

Abstract

Although 4-borono-l-phenylalanine (4-BPA) is currently the only marketed agent available for boron neutron capture therapy (BNCT), its low water solubility raises concerns. In this study, we synthesized 3-borono-l-phenylalanine (3-BPA), a positional isomer of 4-BPA, with improved water solubility. We [...] Read more.

Although 4-borono-l-phenylalanine (4-BPA) is currently the only marketed agent available for boron neutron capture therapy (BNCT), its low water solubility raises concerns. In this study, we synthesized 3-borono-l-phenylalanine (3-BPA), a positional isomer of 4-BPA, with improved water solubility. We further evaluated its physicochemical properties, tumor accumulation, and biodistribution. The water solubility of 3-BPA was 125 g/L, which is more than 100 times higher than that of 4-BPA. Due to the high water solubility, we prepared the administration solution of 3-BPA without a solubilizer sugar, which is inevitably added to 4-BPA preparation and has adverse effects. In in vitro and in vivo experiments, boron accumulation in cancers after administration was statistically equivalent in both sugar-complexed 3-BPA and 4-BPA. Furthermore, the biodistribution of 3-BPA was comparable with that of sugar-complexed 3-BPA. Since 3-BPA has high water solubility and tumor targetability equivalent to 4-BPA, 3-BPA can replace 4-BPA in future BNCT. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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27 pages, 3308 KiB

Open AccessArticle

Persistent Properties of a Subpopulation of Cancer Cells Overexpressing the Hedgehog Receptor Patched

by Álvaro Javier Feliz Morel, Anida Hasanovic, Aurélie Morin, Chloé Prunier, Virginie Magnone, Kevin Lebrigand, Amaury Aouad, Sarah Cogoluegnes, Judith Favier, Claude Pasquier and Isabelle Mus-Veteau

Pharmaceutics 2022, 14(5), 988; https://doi.org/10.3390/pharmaceutics14050988 - 05 May 2022

Cited by 3 | Viewed by 2319

Abstract

Despite the development of new therapeutic strategies, cancer remains one of the leading causes of mortality worldwide. One of the current major challenges is the resistance of cancers to chemotherapy treatments inducing metastases and relapse of the tumor. The Hedgehog receptor Patched (Ptch1) [...] Read more.

Despite the development of new therapeutic strategies, cancer remains one of the leading causes of mortality worldwide. One of the current major challenges is the resistance of cancers to chemotherapy treatments inducing metastases and relapse of the tumor. The Hedgehog receptor Patched (Ptch1) is overexpressed in many types of cancers. We showed that Ptch1 contributes to the efflux of doxorubicin and plays an important role in the resistance to chemotherapy in adrenocortical carcinoma (ACC), a rare cancer which presents strong resistance to the standard of care chemotherapy treatment. In the present study, we isolated and characterized a subpopulation of the ACC cell line H295R in which Ptch1 is overexpressed and more present at the cell surface. This cell subpopulation is more resistant to doxorubicin, grows as spheroids, and has a greater capability of clonogenicity, migration, and invasion than the parental cells. Xenograft experiments performed in mice and in ovo showed that this cell subpopulation is more tumorigenic and metastatic than the parental cells. These results suggest that this cell subpopulation has cancer stem-like or persistent cell properties which were strengthened by RNA-seq. If present in tumors from ACC patients, these cells could be responsible for therapy resistance, relapse, and metastases. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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15 pages, 3497 KiB

Open AccessArticle

CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

by Yan Fu, Hongfei Ci, Wei Du, Qiongzhu Dong and Huliang Jia

Pharmaceutics 2022, 14(2), 275; https://doi.org/10.3390/pharmaceutics14020275 - 25 Jan 2022

Cited by 8 | Viewed by 2442

Abstract

Hepatocellular carcinoma (HCC) is a major health concern worldwide. A better understanding of the mechanisms underlying the malignant phenotype is necessary for developing novel therapeutic strategies for HCC. Signaling pathways initiated by neurotransmitter receptors, such as α5-nicotinic acetylcholine receptor (CHRNA5), have been reported [...] Read more.

Hepatocellular carcinoma (HCC) is a major health concern worldwide. A better understanding of the mechanisms underlying the malignant phenotype is necessary for developing novel therapeutic strategies for HCC. Signaling pathways initiated by neurotransmitter receptors, such as α5-nicotinic acetylcholine receptor (CHRNA5), have been reported to be implicated in tumor progression. However, the functional mechanism of CHRNA5 in HCC remains unclear. In this study, we explored the role of CHRNA5 in HCC and found that CHRNA5 expression was increased in human HCC tissues and positively correlated with the T stage (p < 0.05) and AJCC phase (p < 0.05). The KM plotter database showed that the high expression level of CHRNA5 was strongly associated with worse survival in HCC patients. Both in vitro and in vivo assays showed that CHRNA5 regulates the proliferation ability of HCC by regulating YAP activity. In addition, CHRNA5 promotes the stemness of HCC by regulating stemness-associated genes, such as Nanog, Sox2 and OCT4. Cell migration and invasion assays demonstrated that CHRNA5 significantly enhanced the metastasis of HCC by regulating epithelial–mesenchymal transition (EMT)-associated genes. Furthermore, we found that CHRNA5 regulates the sensitivity of sorafenib in HCC. Our findings suggest that CHRNA5 plays a key role in the progression and drug resistance of HCC, and targeting CHRNA5 may be a strategy for the treatment of HCC. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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24 pages, 6317 KiB

Open AccessArticle

Versatile and Robust Method for Antibody Conjugation to Nanoparticles with High Targeting Efficiency

by Indra Van Zundert, Maria Bravo, Olivier Deschaume, Pierre Cybulski, Carmen Bartic, Johan Hofkens, Hiroshi Uji-i, Beatrice Fortuni and Susana Rocha

Pharmaceutics 2021, 13(12), 2153; https://doi.org/10.3390/pharmaceutics13122153 - 14 Dec 2021

Cited by 4 | Viewed by 3713

Abstract

The application of antibodies in nanomedicine is now standard practice in research since it represents an innovative approach to deliver chemotherapy agents selectively to tumors. The variety of targets or markers that are overexpressed in different types of cancers results in a high [...] Read more.

The application of antibodies in nanomedicine is now standard practice in research since it represents an innovative approach to deliver chemotherapy agents selectively to tumors. The variety of targets or markers that are overexpressed in different types of cancers results in a high demand for antibody conjugated-nanoparticles, which are versatile and easily customizable. Considering up-scaling, the synthesis of antibody-conjugated nanoparticles should be simple and highly reproducible. Here, we developed a facile coating strategy to produce antibody-conjugated nanoparticles using ‘click chemistry’ and further evaluated their selectivity towards cancer cells expressing different markers. Our approach was consistently repeated for the conjugation of antibodies against CD44 and EGFR, which are prominent cancer cell markers. The functionalized particles presented excellent cell specificity towards CD44 and EGFR overexpressing cells, respectively. Our results indicated that the developed coating method is reproducible, versatile, and non-toxic, and can be used for particle functionalization with different antibodies. This grafting strategy can be applied to a wide range of nanoparticles and will contribute to the development of future targeted drug delivery systems. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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27 pages, 6365 KiB

Open AccessArticle

Low Blue Dose Photodynamic Therapy with Porphyrin-Iron Oxide Nanoparticles Complexes: In Vitro Study on Human Melanoma Cells

by Simona Nistorescu, Ana-Maria Udrea, Madalina Andreea Badea, Iulia Lungu, Mihai Boni, Tatiana Tozar, Florian Dumitrache, Valentin-Adrian Maraloiu, Roua Gabriela Popescu, Claudiu Fleaca, Ecaterina Andronescu, Anca Dinischiotu, Angela Staicu and Mihaela Balas

Pharmaceutics 2021, 13(12), 2130; https://doi.org/10.3390/pharmaceutics13122130 - 10 Dec 2021

Cited by 12 | Viewed by 2675

Abstract

The purpose of this study was to investigate the effectiveness in photodynamic therapy of iron oxide nanoparticles (γ-Fe₂O₃ NPs), synthesized by laser pyrolysis technique, functionalized with 5,10,15,20-(Tetra-4-sulfonatophenyl) porphyrin tetraammonium (TPPS) on human cutaneous melanoma cells, after only 1 min blue [...] Read more.

The purpose of this study was to investigate the effectiveness in photodynamic therapy of iron oxide nanoparticles (γ-Fe₂O₃ NPs), synthesized by laser pyrolysis technique, functionalized with 5,10,15,20-(Tetra-4-sulfonatophenyl) porphyrin tetraammonium (TPPS) on human cutaneous melanoma cells, after only 1 min blue light exposure. The efficiency of porphyrin loading on the iron oxide nanocarriers was estimated by using absorption and FTIR spectroscopy. The singlet oxygen yield was determined via transient characteristics of singlet oxygen phosphorescence at 1270 nm both for porphyrin functionalized nanoparticles and rose bengal used as standard. The irradiation was performed with a LED (405 nm, 1 mW/cm²) for 1 min after melanoma cells were treated with TPPS functionalized iron oxide nanoparticles (γ-Fe₂O₃ NPs_TPPS) and incubated for 24 h. Biological tests revealed a high anticancer effect of γ-Fe₂O₃ NPs_TPPS complexes indi-cated by the inhibition of tumor cell proliferation, reduction of cell adhesion, and induction of cell death through ROS generated by TPPS under light exposure. The biological assays were combined with the pharmacokinetic prediction of the porphyrin. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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22 pages, 3243 KiB

Open AccessArticle

Tuning the Cytotoxicity of Bis-Phosphino-Amines Ruthenium(II) Para-Cymene Complexes for Clinical Development in Breast Cancer

by Elena Domínguez-Jurado, Francisco J. Cimas, José Antonio Castro-Osma, Alberto Juan, Agustín Lara-Sánchez, Antonio Rodríguez-Diéguez, Alexandr Shafir, Alberto Ocaña and Carlos Alonso-Moreno

Pharmaceutics 2021, 13(10), 1559; https://doi.org/10.3390/pharmaceutics13101559 - 26 Sep 2021

Cited by 3 | Viewed by 2165

Abstract

Despite some limitations such as long-term side effects or the potential presence of intrinsic or acquired resistance, platinum compounds are key therapeutic components for the treatment of several solid tumors. To overcome these limitations, maintaining the same efficacy, organometallic ruthenium(II) compounds have been [...] Read more.

Despite some limitations such as long-term side effects or the potential presence of intrinsic or acquired resistance, platinum compounds are key therapeutic components for the treatment of several solid tumors. To overcome these limitations, maintaining the same efficacy, organometallic ruthenium(II) compounds have been proposed as a viable alternative to platinum agents as they have a more favorable toxicity profile and represent an ideal template for both, high-throughput and rational drug design. To support the preclinical development of bis-phoshino-amine ruthenium compounds in the treatment of breast cancer, we carried out chemical modifications in the structure of these derivatives with the aim of designing less toxic and more efficient therapeutic agents. We report new bis-phoshino-amine ligands and the synthesis of their ruthenium counterparts. The novel ligands and compounds were fully characterized, water stability analyzed, and their in vitro cytotoxicity against a panel of tumor cell lines representative of different breast cancer subtypes was evaluated. The mechanism of action of the lead compound of the series was explored. In vivo toxicity was also assessed. The results obtained in this article might pave the way for the clinical development of these compounds in breast cancer therapy. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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16 pages, 5291 KiB

Open AccessArticle

Anti-Cancer Nanopowders and MAPLE-Fabricated Thin Films Based on SPIONs Surface Modified with Paclitaxel Loaded β-Cyclodextrin

by Rebecca Alexandra Puiu, Paul Cătălin Balaure, Ema Constantinescu, Alexandru Mihai Grumezescu, Ecaterina Andronescu, Ovidiu-Cristian Oprea, Bogdan Stefan Vasile, Valentina Grumezescu, Irina Negut, Ionela Cristina Nica and Miruna Silvia Stan

Pharmaceutics 2021, 13(9), 1356; https://doi.org/10.3390/pharmaceutics13091356 - 28 Aug 2021

Cited by 19 | Viewed by 2777

Abstract

Globally, cancer is the second most common cause of death, and Europe accounts for almost 25% of the global cancer burden, although its people make up only 10% of the world’s population. Conventional systemically administered anti-cancer drugs come with important drawbacks such as [...] Read more.

Globally, cancer is the second most common cause of death, and Europe accounts for almost 25% of the global cancer burden, although its people make up only 10% of the world’s population. Conventional systemically administered anti-cancer drugs come with important drawbacks such as inefficiency due to poor bioavailability and improper biodistribution, severe side effects associated with low therapeutic indices, and the development of multidrug resistance. Therefore, smart nano-engineered targeted drug-delivery systems with tailored pharmacokinetics and biodistribution which can selectively deliver anti-cancer agents directly to the tumor site are the solution to most difficulties encountered with conventional therapeutic tools. Here, we report on the synthesis, physicochemical characterization, and in vitro evaluation of biocompatibility and anti-tumor activity of novel magnetically targetable SPIONs based on magnetite (Fe₃O₄) nanoparticles’ surface modified with β-cyclodextrin (CD) and paclitaxel (PTX)–guest–host inclusion complexes (Fe₃O₄@β-CD/PTX). Both pristine Fe₃O₄@β-CD nanopowders and PTX-loaded thin films fabricated by MAPLE technique were investigated. Pristine Fe₃O₄@β-CD and Fe₃O₄@β-CD/PTX thin films were physicochemically characterized by X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), thermal analysis, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The biocompatibility of bare magnetic nanocomposite thin films was evaluated by MTT cell viability assay on a normal 3T3 osteoblast cell line culture and by measuring the level of NO in the culture medium. No significant modifications, neither in cell viability nor in NO level, could be observed, thereby demonstrating the excellent biocompatibility of the SPIONs thin films. Inverted phase-contrast microscopy showed no evident adverse effect on the morphology of normal osteoblasts. On the other hand, Fe₃O₄@β-CD/PTX films decreased the cell viability of the MG-63 osteosarcoma cell line by 85%, demonstrating excellent anti-tumor activity. The obtained results recommend these magnetic hybrid films as promising candidates for future delivery, and hyperthermia applications in cancer treatment. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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16 pages, 4310 KiB

Open AccessArticle

Stimuli-Responsive Nanofibers Containing Gold Nanorods for On-Demand Drug Delivery Platforms

by Baljinder Singh, Nutan Shukla, Junkee Kim, Kibeom Kim and Myoung-Hwan Park

Pharmaceutics 2021, 13(8), 1319; https://doi.org/10.3390/pharmaceutics13081319 - 23 Aug 2021

Cited by 26 | Viewed by 3690

Abstract

On-demand drug delivery systems using nanofibers have attracted significant attention owing to their controllable properties for drug release through external stimuli. Near-infrared (NIR)-responsive nanofibers provide a platform where the drug release profile can be achieved by the on-demand supply of drugs at a [...] Read more.

On-demand drug delivery systems using nanofibers have attracted significant attention owing to their controllable properties for drug release through external stimuli. Near-infrared (NIR)-responsive nanofibers provide a platform where the drug release profile can be achieved by the on-demand supply of drugs at a desired dose for cancer therapy. Nanomaterials such as gold nanorods (GNRs) exhibit absorbance in the NIR range, and in response to NIR irradiation, they generate heat as a result of a plasmon resonance effect. In this study, we designed poly (N-isopropylacrylamide) (PNIPAM) composite nanofibers containing GNRs. PNIPAM is a heat-reactive polymer that provides a swelling and deswelling property to the nanofibers. Electrospun nanofibers have a large surface-area-to-volume ratio, which is used to effectively deliver large quantities of drugs. In this platform, both hydrophilic and hydrophobic drugs can be introduced and manipulated. On-demand drug delivery systems were obtained through stimuli-responsive nanofibers containing GNRs and PNIPAM. Upon NIR irradiation, the heat generated by the GNRs ensures shrinking of the nanofibers owing to the thermal response of PNIPAM, thereby resulting in a controlled drug release. The versatility of the light-responsive nanofibers as a drug delivery platform was confirmed in cell studies, indicating the advantages of the swelling and deswelling property of the nanofibers and on–off drug release behavior with good biocompatibility. In addition, the system has potential for the combination of chemotherapy with multiple drugs to enhance the effectiveness of complex cancer treatments. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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13 pages, 3963 KiB

Open AccessArticle

Light- and Melanin Nanoparticle-Induced Cytotoxicity in Metastatic Cancer Cells

by Victoria R. Gabriele, Robabeh M. Mazhabi, Natalie Alexander, Purna Mukherjee, Thomas N. Seyfried, Njemuwa Nwaji, Eser M. Akinoglu, Andrzej Mackiewicz, Guofu Zhou, Michael Giersig, Michael J. Naughton and Krzysztof Kempa

Pharmaceutics 2021, 13(7), 965; https://doi.org/10.3390/pharmaceutics13070965 - 26 Jun 2021

Cited by 6 | Viewed by 2420

Abstract

Melanin nanoparticles are known to be biologically benign to human cells for a wide range of concentrations in a high glucose culture nutrition. Here, we show cytotoxic behavior at high nanoparticle and low glucose concentrations, as well as at low nanoparticle concentration under [...] Read more.

Melanin nanoparticles are known to be biologically benign to human cells for a wide range of concentrations in a high glucose culture nutrition. Here, we show cytotoxic behavior at high nanoparticle and low glucose concentrations, as well as at low nanoparticle concentration under exposure to (nonionizing) visible radiation. To study these effects in detail, we developed highly monodispersed melanin nanoparticles (both uncoated and glucose-coated). In order to study the effect of significant cellular uptake of these nanoparticles, we employed three cancer cell lines: VM-M3, A375 (derived from melanoma), and HeLa, all known to exhibit strong macrophagic character, i.e., strong nanoparticle uptake through phagocytic ingestion. Our main observations are: (i) metastatic VM-M3 cancer cells massively ingest melanin nanoparticles (mNPs); (ii) the observed ingestion is enhanced by coating mNPs with glucose; (iii) after a certain level of mNP ingestion, the metastatic cancer cells studied here are observed to die—glucose coating appears to slow that process; (iv) cells that accumulate mNPs are much more susceptible to killing by laser illumination than cells that do not accumulate mNPs; and (v) non-metastatic VM-NM1 cancer cells also studied in this work do not ingest the mNPs, and remain unaffected after receiving identical optical energy levels and doses. Results of this study could lead to the development of a therapy for control of metastatic stages of cancer. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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22 pages, 7702 KiB

Open AccessArticle

Investigation on the Composition of Agarose–Collagen I Blended Hydrogels as Matrices for the Growth of Spheroids from Breast Cancer Cell Lines

by Alessandra Quarta, Nunzia Gallo, Daniele Vergara, Luca Salvatore, Concetta Nobile, Andrea Ragusa and Antonio Gaballo

Pharmaceutics 2021, 13(7), 963; https://doi.org/10.3390/pharmaceutics13070963 - 26 Jun 2021

Cited by 16 | Viewed by 3026

Abstract

Three-dimensional (3D) cell culture systems mimic the structural complexity of the tissue microenvironment and are gaining increasing importance as they resemble the extracellular matrix (ECM)–cell and cell–cell physical interactions occurring in vivo. Several scaffold-based culture systems have been already proposed as valuable tools [...] Read more.

Three-dimensional (3D) cell culture systems mimic the structural complexity of the tissue microenvironment and are gaining increasing importance as they resemble the extracellular matrix (ECM)–cell and cell–cell physical interactions occurring in vivo. Several scaffold-based culture systems have been already proposed as valuable tools for large-scale production of spheroids, but they often suffer of poor reproducibility or high costs of production. In this work, we present a reliable 3D culture system based on collagen I-blended agarose hydrogels and show how the variation in the agarose percentage affects the physical and mechanical properties of the resulting hydrogel. The influence of the different physical and mechanical properties of the blended hydrogels on the growth, size, morphology, and cell motility of the spheroids obtained by culturing three different breast cancer cell lines (MCF-7, MDA-MB-361, and MDA-MB-231) was also evaluated. As proof of concept, the cisplatin penetration and its cytotoxic effect on the tumor spheroids as function of the hydrogel stiffness were also investigated. Noteworthily, the possibility to recover the spheroids from the hydrogels for further processing and other biological studies has been considered. This feature, in addition to the ease of preparation, the lack of cross-linking chemistry and the high reproducibility, makes this hydrogel a reliable biomimetic matrix for the growth of 3D cell structures. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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14 pages, 2058 KiB

Open AccessArticle

Effects of Lapatinib on HER2-Positive and HER2-Negative Canine Mammary Carcinoma Cells Cultured In Vitro

by Antonio Fernando Leis-Filho, Patrícia de Faria Lainetti, Priscila Emiko Kobayashi, Carlos Eduardo Fonseca-Alves and Renée Laufer-Amorim

Pharmaceutics 2021, 13(6), 897; https://doi.org/10.3390/pharmaceutics13060897 - 17 Jun 2021

Cited by 4 | Viewed by 2585

Abstract

HER2 is a prognostic and predictive marker widely used in breast cancer. Lapatinib is a tyrosine kinase inhibitor that works by blocking the phosphorylation of the receptor HER2. Its use is related to relatively good results in the treatment of women with HER2+ [...] Read more.

HER2 is a prognostic and predictive marker widely used in breast cancer. Lapatinib is a tyrosine kinase inhibitor that works by blocking the phosphorylation of the receptor HER2. Its use is related to relatively good results in the treatment of women with HER2+ breast cancer. Thus, this study aimed to verify the effects of lapatinib on four canine primary mammary gland carcinoma cell cultures and two paired metastatic cell cultures. Cultures were treated with lapatinib at concentrations of 100, 500, 1000 and 3000 nM for 24 h and the 50% inhibitory concentration (IC₅₀) for each cell culture was determined. In addition, a transwell assay was performed to assess the ability of lapatinib to inhibit cell migration. Furthermore, we verified HER2 expression by RT-qPCR analysis of cell cultures and formalin-fixed paraffin-embedded tissues from samples corresponding to those used in cell culture. Lapatinib was able to inhibit cell proliferation in all cell cultures, but it was not able to inhibit migration in all cell cultures. The higher the expression of HER2 in a culture, the more sensitive the culture was to treatment. This relationship may be an indication that the expression of HER2 may be a predictive factor and opens a new perspective for the treatment of primary and metastatic mammary gland cancer. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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16 pages, 4675 KiB

Open AccessArticle

Growth Inhibitory Effects of Ester Derivatives of Menahydroquinone-4, the Reduced Form of Vitamin K₂₍₂₀₎, on All-Trans Retinoic Acid-Resistant HL60 Cell Line

by Hirofumi Yamakawa, Shuichi Setoguchi, Shotaro Goto, Daisuke Watase, Kazuki Terada, Nami Nagata-Akaho, Erina Toki, Mitsuhisa Koga, Kazuhisa Matsunaga, Yoshiharu Karube and Jiro Takata

Pharmaceutics 2021, 13(5), 758; https://doi.org/10.3390/pharmaceutics13050758 - 20 May 2021

Cited by 5 | Viewed by 2604

Abstract

The first-choice drug for acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA), frequently causes drug-resistance and some adverse effects. Thus, an effective and safe agent for ATRA-resistant APL is needed. Menaquinone-4 (MK-4, vitamin K₂₍₂₀₎), used for osteoporosis treatment, does not have [...] Read more.

The first-choice drug for acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA), frequently causes drug-resistance and some adverse effects. Thus, an effective and safe agent for ATRA-resistant APL is needed. Menaquinone-4 (MK-4, vitamin K₂₍₂₀₎), used for osteoporosis treatment, does not have serious adverse effects. It has been reported that MK-4 has growth-inhibitory effects on HL60 cells by inducing apoptosis via the activation of Bcl-2 antagonist killer 1 (BAK). However, the effect of MK-4 on ATRA-resistant APL has not been reported. Here, we show that ester derivatives of menahydroquinone-4 (MKH; a reduced form of MK-4), MKH 1,4-bis-N,N-dimethylglycinate (MKH-DMG) and MKH 1,4-bis-hemi-succinate (MKH-SUC), exerted strong growth-inhibitory effects even on ATRA-resistant HL60 (HL-60R) cells compared with ATRA and MK-4. MKH delivery after MKH-SUC treatment was higher than that after MK-4 treatment, and the results indicated apoptosis induced by BAK activation. In contrast, for MKH-DMG, reconversion to MKH was slow and apoptosis was not observed. We suggest that the ester forms, including monoesters of MKH-DMG, exhibit another mechanism independent of apoptosis. In conclusion, the MKH derivatives (MKH-SUC and MKH-DMG) inhibited not only HL60 cells but also HL-60R cells, indicating a potential to overcome ATRA resistance. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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21 pages, 3984 KiB

Open AccessArticle

Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis

by Surinder M. Soond, Lyudmila V. Savvateeva, Vladimir A. Makarov, Neonila V. Gorokhovets, Paul A. Townsend and Andrey A. Zamyatnin, Jr.

Pharmaceutics 2021, 13(3), 339; https://doi.org/10.3390/pharmaceutics13030339 - 05 Mar 2021

Cited by 8 | Viewed by 3507

Abstract

Certain lysosomal cathepsin proteins have come into focus as being good candidates for therapeutic targeting, based on them being over-expressed in a variety of cancers and based on their regulation of the apoptotic pathway. Here, we report novel findings that highlight the ability [...] Read more.

Certain lysosomal cathepsin proteins have come into focus as being good candidates for therapeutic targeting, based on them being over-expressed in a variety of cancers and based on their regulation of the apoptotic pathway. Here, we report novel findings that highlight the ability of cathepsin S expression to be up-regulated under Paclitaxel-stimulatory conditions in kidney cell lines and it being able to cleave the apoptotic p21 BAX protein in intact cells and in vitro. Consistent with this, we demonstrate that this effect can be abrogated in vitro and in mammalian cells under conditions that utilize dominant-inhibitory cathepsin S expression, cathepsin S expression-knockdown and through the activity of a novel peptide inhibitor, CS-PEP1. Moreover, we report a unique role for cathepsin S in that it can cleave a polyubiquitinated-BAX protein intermediate and is a step that may contribute to down-regulating post-translationally-modified levels of BAX protein. Finally, CS-PEP1 may possess promising activity as a potential anti-cancer therapeutic against chemotherapeutic-resistant Renal Clear Cell Carcinoma kidney cancer cells and for combined uses with therapeutics such as Paclitaxel. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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Review

Jump to: Editorial, Research

30 pages, 1436 KiB

Open AccessReview

Indole Antitumor Agents in Nanotechnology Formulations: An Overview

by Eleonora Russo, Carola Grondona, Chiara Brullo, Andrea Spallarossa, Carla Villa and Bruno Tasso

Pharmaceutics 2023, 15(7), 1815; https://doi.org/10.3390/pharmaceutics15071815 - 25 Jun 2023

Viewed by 1484

Abstract

The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different therapeutic areas. Due to its varied biological activities, high unique chemical properties and significant pharmacological behaviors, indole derivatives [...] Read more.

The indole heterocycle represents one of the most important scaffolds in medicinal chemistry and is shared among a number of drugs clinically used in different therapeutic areas. Due to its varied biological activities, high unique chemical properties and significant pharmacological behaviors, indole derivatives have drawn considerable interest in the last decade as antitumor agents active against different types of cancers. The research of novel antiproliferative drugs endowed with enhanced efficacy and reduced toxicity led to the approval by U.S. Food and Drug Administration of the indole-based anticancer agents Sunitinib, Nintedanib, Osimertinib, Panobinostat, Alectinib and Anlotinib. Additionally, new drug delivery systems have been developed to protect the active principle from degradation and to direct the drug to the specific site for clinical use, thus reducing its toxicity. In the present work is an updated review of the recently approved indole-based anti-cancer agents and the nanotechnology systems developed for their delivery. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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23 pages, 2112 KiB

Open AccessReview

Precision Anti-Cancer Medicines by Oligonucleotide Therapeutics in Clinical Research Targeting Undruggable Proteins and Non-Coding RNAs

by Damiano Bartolucci, Andrea Pession, Patrizia Hrelia and Roberto Tonelli

Pharmaceutics 2022, 14(7), 1453; https://doi.org/10.3390/pharmaceutics14071453 - 12 Jul 2022

Cited by 7 | Viewed by 3011

Abstract

Cancer incidence and mortality continue to increase, while the conventional chemotherapeutic drugs confer limited efficacy and relevant toxic side effects. Novel strategies are urgently needed for more effective and safe therapeutics in oncology. However, a large number of proteins are considered undruggable by [...] Read more.

Cancer incidence and mortality continue to increase, while the conventional chemotherapeutic drugs confer limited efficacy and relevant toxic side effects. Novel strategies are urgently needed for more effective and safe therapeutics in oncology. However, a large number of proteins are considered undruggable by conventional drugs, such as the small molecules. Moreover, the mRNA itself retains oncological functions, and its targeting offers the double advantage of blocking the tumorigenic activities of the mRNA and the translation into protein. Finally, a large family of non-coding RNAs (ncRNAs) has recently emerged that are also dysregulated in cancer, but they could not be targeted by drugs directed against the proteins. In this context, this review describes how the oligonucleotide therapeutics targeting RNA or DNA sequences, are emerging as a new class of drugs, able to tackle the limitations described above. Numerous clinical trials are evaluating oligonucleotides for tumor treatment, and in the next few years some of them are expected to reach the market. We describe the oligonucleotide therapeutics targeting undruggable proteins (focusing on the most relevant, such as those originating from the MYC and RAS gene families), and for ncRNAs, in particular on those that are under clinical trial evaluation in oncology. We highlight the challenges and solutions for the clinical success of oligonucleotide therapeutics, with particular emphasis on the peculiar challenges that render it arduous to treat tumors, such as heterogeneity and the high mutation rate. In the review are presented these and other advantages offered by the oligonucleotide as an emerging class of biotherapeutics for a new era of precision anti-cancer medicine. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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11 pages, 1502 KiB

Open AccessReview

BUB3, beyond the Simple Role of Partner

by Patrícia M. A. Silva and Hassan Bousbaa

Pharmaceutics 2022, 14(5), 1084; https://doi.org/10.3390/pharmaceutics14051084 - 18 May 2022

Cited by 7 | Viewed by 2466

Abstract

The BUB3 protein plays a key role in the activation of the spindle assembly checkpoint (SAC), a ubiquitous surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis and, consequently, prevents chromosome mis-segregation and aneuploidy. Besides its role in SAC signaling, BUB3 [...] Read more.

The BUB3 protein plays a key role in the activation of the spindle assembly checkpoint (SAC), a ubiquitous surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis and, consequently, prevents chromosome mis-segregation and aneuploidy. Besides its role in SAC signaling, BUB3 regulates chromosome attachment to the spindle microtubules. It is also involved in telomere replication and maintenance. Deficiency of the BUB3 gene has been closely linked to premature aging. Upregulation of the BUB3 gene has been found in a variety of human cancers and is associated with poor prognoses. Here, we review the structure and functions of BUB3 in mitosis, its expression in cancer and association with survival prognoses, and its potential as an anticancer target. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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19 pages, 765 KiB

Open AccessReview

Therapeutic Vaccines Targeting Neoantigens to Induce T-Cell Immunity against Cancers

by Shih-Cheng Pao, Mu-Tzu Chu and Shuen-Iu Hung

Pharmaceutics 2022, 14(4), 867; https://doi.org/10.3390/pharmaceutics14040867 - 15 Apr 2022

Cited by 8 | Viewed by 3534

Abstract

Cancer immunotherapy has achieved multiple clinical benefits and has become an indispensable component of cancer treatment. Targeting tumor-specific antigens, also known as neoantigens, plays a crucial role in cancer immunotherapy. T cells of adaptive immunity that recognize neoantigens, but do not induce unwanted [...] Read more.

Cancer immunotherapy has achieved multiple clinical benefits and has become an indispensable component of cancer treatment. Targeting tumor-specific antigens, also known as neoantigens, plays a crucial role in cancer immunotherapy. T cells of adaptive immunity that recognize neoantigens, but do not induce unwanted off-target effects, have demonstrated high efficacy and low side effects in cancer immunotherapy. Tumor neoantigens derived from accumulated genetic instability can be characterized using emerging technologies, such as high-throughput sequencing, bioinformatics, predictive algorithms, mass-spectrometry analyses, and immunogenicity validation. Neoepitopes with a higher affinity for major histocompatibility complexes can be identified and further applied to the field of cancer vaccines. Therapeutic vaccines composed of tumor lysates or cells and DNA, mRNA, or peptides of neoantigens have revoked adaptive immunity to kill cancer cells in clinical trials. Broad clinical applicability of these therapeutic cancer vaccines has emerged. In this review, we discuss recent progress in neoantigen identification and applications for cancer vaccines and the results of ongoing trials. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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25 pages, 4861 KiB

Open AccessReview

Current Status of the Use of Multifunctional Enzymes as Anti-Cancer Drug Targets

by Carla S. S. Teixeira and Sérgio F. Sousa

Pharmaceutics 2022, 14(1), 10; https://doi.org/10.3390/pharmaceutics14010010 - 21 Dec 2021

Cited by 10 | Viewed by 3248

Abstract

Fighting cancer is one of the major challenges of the 21st century. Among recently proposed treatments, molecular-targeted therapies are attracting particular attention. The potential targets of such therapies include a group of enzymes that possess the capability to catalyze at least two different [...] Read more.

Fighting cancer is one of the major challenges of the 21st century. Among recently proposed treatments, molecular-targeted therapies are attracting particular attention. The potential targets of such therapies include a group of enzymes that possess the capability to catalyze at least two different reactions, so-called multifunctional enzymes. The features of such enzymes can be used to good advantage in the development of potent selective inhibitors. This review discusses the potential of multifunctional enzymes as anti-cancer drug targets along with the current status of research into four enzymes which by their inhibition have already demonstrated promising anti-cancer effects in vivo, in vitro, or both. These are PFK-2/FBPase-2 (involved in glucose homeostasis), ATIC (involved in purine biosynthesis), LTA₄H (involved in the inflammation process) and Jmjd6 (involved in histone and non-histone posttranslational modifications). Currently, only LTA₄H and PFK-2/FBPase-2 have inhibitors in active clinical development. However, there are several studies proposing potential inhibitors targeting these four enzymes that, when used alone or in association with other drugs, may provide new alternatives for preventing cancer cell growth and proliferation and increasing the life expectancy of patients. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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26 pages, 2603 KiB

Open AccessReview

Signaling Pathway Inhibitors, miRNA, and Nanocarrier-Based Pharmacotherapeutics for the Treatment of Lung Cancer: A Review

by Shadab Md, Nabil A. Alhakamy, Shahid Karim, Gamal A Gabr, Mohammad Kashif Iqubal and Samar S. A. Murshid

Pharmaceutics 2021, 13(12), 2120; https://doi.org/10.3390/pharmaceutics13122120 - 08 Dec 2021

Cited by 5 | Viewed by 2851

Abstract

Lung cancer is one of the most commonly diagnosed cancers and is responsible for a large number of deaths worldwide. The pathogenic mechanism of lung cancer is complex and multifactorial in origin. Thus, various signaling pathways as targets for therapy are being examined, [...] Read more.

Lung cancer is one of the most commonly diagnosed cancers and is responsible for a large number of deaths worldwide. The pathogenic mechanism of lung cancer is complex and multifactorial in origin. Thus, various signaling pathways as targets for therapy are being examined, and many new drugs are in the pipeline. However, both conventional and target-based drugs have been reported to present significant adverse effects, and both types of drugs can affect the clinical outcome in addition to patient quality of life. Recently, miRNA has been identified as a promising target for lung cancer treatment. Therefore, miRNA mimics, oncomiRs, or miRNA suppressors have been developed and studied for possible anticancer effects. However, these miRNAs also suffer from the limitations of low stability, biodegradation, thermal instability, and other issues. Thus, nanocarrier-based drug delivery for the chemotherapeutic drug delivery in addition to miRNA-based systems have been developed so that existing limitations can be resolved, and enhanced therapeutic outcomes can be achieved. Thus, this review discusses lung cancer’s molecular mechanism, currently approved drugs, and their adverse effects. We also discuss miRNA biosynthesis and pathogenetic role, highlight pre-clinical and clinical evidence for use of miRNA in cancer therapy, and discussed limitations of this therapy. Furthermore, nanocarrier-based drug delivery systems to deliver chemotherapeutic drugs and miRNAs are described in detail. In brief, the present review describes the mechanism and up-to-date possible therapeutic approaches for lung cancer treatment and emphasizes future prospects to bring these novel approaches from bench to bedside. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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17 pages, 1010 KiB

Open AccessReview

Immunotherapy for Triple-Negative Breast Cancer

by Yifeng Cao, Chuyang Chen, Yi Tao, Weifeng Lin and Ping Wang

Pharmaceutics 2021, 13(12), 2003; https://doi.org/10.3390/pharmaceutics13122003 - 25 Nov 2021

Cited by 16 | Viewed by 3615

Abstract

Triple-negative breast cancer (TNBC) is characterized by extensive tumor heterogeneity at both the pathologic and molecular levels, particularly accelerated aggressiveness, and terrible metastasis. It is responsible for the increased mortality of breast cancer patients. Due to the negative expression of estrogen receptors, progesterone [...] Read more.

Triple-negative breast cancer (TNBC) is characterized by extensive tumor heterogeneity at both the pathologic and molecular levels, particularly accelerated aggressiveness, and terrible metastasis. It is responsible for the increased mortality of breast cancer patients. Due to the negative expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2, the progress of targeted therapy has been hindered. Higher immune response in TNBCs than for other breast cancer types makes immunotherapy suitable for TNBC therapy. At present, promising treatments in immunotherapy of TNBC include immune checkpoints (ICs) blockade therapy, adoptive T-cell immunotherapy, and tumor vaccine immunotherapy. In addition, nanomedicines exhibit great potential in cancer therapy through the enhanced permeability and retention (EPR) effect. Immunotherapy-involved combination therapy may exert synergistic effects by combining with other treatments, such as traditional chemotherapy and new treatments, including photodynamic therapy (PTT), photodynamic therapy (PDT), and sonodynamic therapy (SDT). This review focuses on introducing the principles and latest development as well as progress in using nanocarriers as drug-delivery systems for the immunotherapy of TNBC. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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51 pages, 2005 KiB

Open AccessReview

Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design

by Zdeněk Kejík, Robert Kaplánek, Petr Dytrych, Michal Masařík, Kateřina Veselá, Nikita Abramenko, David Hoskovec, Martina Vašáková, Jarmila Králová, Pavel Martásek and Milan Jakubek

Pharmaceutics 2021, 13(11), 1879; https://doi.org/10.3390/pharmaceutics13111879 - 05 Nov 2021

Cited by 11 | Viewed by 6259

Abstract

Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells [...] Read more.

Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death. This review discusses the impact of NSCLC therapy strategies based on a meta-analysis of clinical studies. In addition, possible therapeutic strategies for repression when standard methods fail, such as the administration of low-toxicity natural anticancer agents targeting these phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in the context of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis (mechanisms related to tumour-associated and -infiltrating cells, epithelial–mesenchymal transition, and migration of cancer cells). Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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17 pages, 9329 KiB

Open AccessReview

Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

by Adriana G. Quiroz-Reyes, Paulina Delgado-Gonzalez, Jose Francisco Islas, Juan Luis Delgado Gallegos, Javier Humberto Martínez Garza and Elsa N. Garza-Treviño

Pharmaceutics 2021, 13(7), 1062; https://doi.org/10.3390/pharmaceutics13071062 - 10 Jul 2021

Cited by 11 | Viewed by 2909

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and [...] Read more.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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45 pages, 10628 KiB

Open AccessReview

Second-Generation Antimitotics in Cancer Clinical Trials

by Pedro Novais, Patrícia M. A. Silva, Isabel Amorim and Hassan Bousbaa

Pharmaceutics 2021, 13(7), 1011; https://doi.org/10.3390/pharmaceutics13071011 - 02 Jul 2021

Cited by 27 | Viewed by 3813

Abstract

Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged [...] Read more.

Mitosis represents a promising target to block cancer cell proliferation. Classical antimitotics, mainly microtubule-targeting agents (MTAs), such as taxanes and vinca alkaloids, are amongst the most successful anticancer drugs. By disrupting microtubules, they activate the spindle assembly checkpoint (SAC), which induces a prolonged delay in mitosis, expected to induce cell death. However, resistance, toxicity, and slippage limit the MTA’s effectiveness. With the desire to overcome some of the MTA’s limitations, mitotic and SAC components have attracted great interest as promising microtubule-independent targets, leading to the so-called second-generation antimitotics (SGAs). The identification of inhibitors against most of these targets, and the promising outcomes achieved in preclinical assays, has sparked the interest of academia and industry. Many of these inhibitors have entered clinical trials; however, they exhibited limited efficacy as monotherapy, and failed to go beyond phase II trials. Combination therapies are emerging as promising strategies to give a second chance to these SGAs. Here, an updated view of the SGAs that reached clinical trials is here provided, together with future research directions, focusing on inhibitors that target the SAC components. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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13 pages, 594 KiB

Open AccessReview

Cell-Penetrating Peptides: Applications in Tumor Diagnosis and Therapeutics

by Jeffrey Stiltner, Kayla McCandless and Maliha Zahid

Pharmaceutics 2021, 13(6), 890; https://doi.org/10.3390/pharmaceutics13060890 - 15 Jun 2021

Cited by 28 | Viewed by 3912

Abstract

Since their identification over twenty-five years ago, the plethora of cell-penetrating peptides (CPP) and their applications has skyrocketed. These 5 to 30 amino acid in length peptides have the unique property of breaching the cell membrane barrier while carrying cargoes larger than themselves [...] Read more.

Since their identification over twenty-five years ago, the plethora of cell-penetrating peptides (CPP) and their applications has skyrocketed. These 5 to 30 amino acid in length peptides have the unique property of breaching the cell membrane barrier while carrying cargoes larger than themselves into cells in an intact, functional form. CPPs can be conjugated to fluorophores, activatable probes, radioisotopes or contrast agents for imaging tissues, such as tumors. There is no singular mechanism for translocation of CPPs into a cell, and therefore, many CPPs are taken up by a multitude of cell types, creating the challenge of tumor-specific translocation and hindering clinical effectiveness. Varying strategies have been developed to combat this issue and enhance their diagnostic potential by derivatizing CPPs for better targeting by constructing specific cell-activated forms. These methods are currently being used to image integrin-expressing tumors, breast cancer cells, human histiocytic lymphoma and protease-secreting fibrosarcoma cells, to name a few. Additionally, identifying safe, effective therapeutics for malignant tumors has long been an active area of research. CPPs can circumvent many of the complications found in treating cancer with conventional therapeutics by targeted delivery of drugs into tumors, thereby decreasing off-target side effects, a feat not achievable by currently employed conventional chemotherapeutics. Myriad types of chemotherapeutics such as tyrosine kinase inhibitors, antitumor antibodies and nanoparticles can be functionally attached to these peptides, leading to the possibility of delivering established and novel cancer therapeutics directly to tumor tissue. While much research is needed to overcome potential issues with these peptides, they offer a significant advancement over current mechanisms to treat cancer. In this review, we present a brief overview of the research, leading to identification of CPPs with a comprehensive state-of-the-art review on the role of these novel peptides in both cancer diagnostics as well as therapeutics. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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24 pages, 2303 KiB

Open AccessReview

Recent Progress in Lipid Nanoparticles for Cancer Theranostics: Opportunity and Challenges

by Sarah I. Bukhari, Syed Sarim Imam, Mohammad Zaki Ahmad, Parameswara Rao Vuddanda, Sultan Alshehri, Wael A. Mahdi and Javed Ahmad

Pharmaceutics 2021, 13(6), 840; https://doi.org/10.3390/pharmaceutics13060840 - 07 Jun 2021

Cited by 31 | Viewed by 4855

Abstract

Cancer is one of the major leading causes of mortality in the world. The implication of nanotherapeutics in cancer has garnered splendid attention owing to their capability to efficiently address various difficulties associated with conventional drug delivery systems such as non-specific biodistribution, poor [...] Read more.

Cancer is one of the major leading causes of mortality in the world. The implication of nanotherapeutics in cancer has garnered splendid attention owing to their capability to efficiently address various difficulties associated with conventional drug delivery systems such as non-specific biodistribution, poor efficacy, and the possibility of occurrence of multi-drug resistance. Amongst a plethora of nanocarriers for drugs, this review emphasized lipidic nanocarrier systems for delivering anticancer therapeutics because of their biocompatibility, safety, high drug loading and capability to simultaneously carrying imaging agent and ligands as well. Furthermore, to date, the lack of interaction between diagnosis and treatment has hampered the efforts of the nanotherapeutic approach alone to deal with cancer effectively. Therefore, a novel paradigm with concomitant imaging (with contrasting agents), targeting (with biomarkers), and anticancer agent being delivered in one lipidic nanocarrier system (as cancer theranostics) seems to be very promising in overcoming various hurdles in effective cancer treatment. The major obstacles that are supposed to be addressed by employing lipidic theranostic nanomedicine include nanomedicine reach to tumor cells, drug internalization in cancer cells for therapeutic intervention, off-site drug distribution, and uptake via the host immune system. A comprehensive account of recent research updates in the field of lipidic nanocarrier loaded with therapeutic and diagnostic agents is covered in the present article. Nevertheless, there are notable hurdles in the clinical translation of the lipidic theranostic nanomedicines, which are also highlighted in the present review along with plausible countermeasures. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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21 pages, 700 KiB

Open AccessReview

A Review of Repurposed Cancer Drugs in Clinical Trials for Potential Treatment of COVID-19

by Bárbara Costa and Nuno Vale

Pharmaceutics 2021, 13(6), 815; https://doi.org/10.3390/pharmaceutics13060815 - 30 May 2021

Cited by 10 | Viewed by 3878

Abstract

The pandemic of the coronavirus disease 2019 (COVID-19) represents an unprecedented challenge to identify effective drugs for prevention and treatment. While the world’s attention is focused on news of COVID-19 vaccine updates, clinical management still requires improvement. Due to the similarity of cancer-induced [...] Read more.

The pandemic of the coronavirus disease 2019 (COVID-19) represents an unprecedented challenge to identify effective drugs for prevention and treatment. While the world’s attention is focused on news of COVID-19 vaccine updates, clinical management still requires improvement. Due to the similarity of cancer-induced inflammation, immune dysfunction, and coagulopathy to COVID-19, anticancer drugs, such as Interferon, Pembrolizumab or Bicalutamide, are already being tested in clinical trials for repurposing, alone or in combination. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected, clinicians need effective medical treatments for this infection. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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28 pages, 1228 KiB

Open AccessReview

Oncogenic and Tumor Suppressive Components of the Cell Cycle in Breast Cancer Progression and Prognosis

by Dharambir Kashyap, Vivek Kumar Garg, Elise N. Sandberg, Neelam Goel and Anupam Bishayee

Pharmaceutics 2021, 13(4), 569; https://doi.org/10.3390/pharmaceutics13040569 - 17 Apr 2021

Cited by 32 | Viewed by 3857

Abstract

Cancer, a disease of inappropriate cell proliferation, is strongly interconnected with the cell cycle. All cancers consist of an abnormal accumulation of neoplastic cells, which are propagated toward uncontrolled cell division and proliferation in response to mitogenic signals. Mitogenic stimuli include genetic and [...] Read more.

Cancer, a disease of inappropriate cell proliferation, is strongly interconnected with the cell cycle. All cancers consist of an abnormal accumulation of neoplastic cells, which are propagated toward uncontrolled cell division and proliferation in response to mitogenic signals. Mitogenic stimuli include genetic and epigenetic changes in cell cycle regulatory genes and other genes which regulate the cell cycle. This suggests that multiple, distinct pathways of genetic alterations lead to cancer development. Products of both oncogenes (including cyclin-dependent kinase (CDKs) and cyclins) and tumor suppressor genes (including cyclin-dependent kinase inhibitors) regulate cell cycle machinery and promote or suppress cell cycle progression, respectively. The identification of cyclins and CDKs help to explain and understand the molecular mechanisms of cell cycle machinery. During breast cancer tumorigenesis, cyclins A, B, C, D1, and E; cyclin-dependent kinase (CDKs); and CDK-inhibitor proteins p16, p21, p27, and p53 are known to play significant roles in cell cycle control and are tightly regulated in normal breast epithelial cells. Following mitogenic stimuli, these components are deregulated, which promotes neoplastic transformation of breast epithelial cells. Multiple studies implicate the roles of both types of components—oncogenic CDKs and cyclins, along with tumor-suppressing cyclin-dependent inhibitors—in breast cancer initiation and progression. Numerous clinical studies have confirmed that there is a prognostic significance for screening for these described components, regarding patient outcomes and their responses to therapy. The aim of this review article is to summarize the roles of oncogenic and tumor-suppressive components of the cell cycle in breast cancer progression and prognosis. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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22 pages, 1856 KiB

Open AccessReview

Chronicles of Nanoerythrosomes: An Erythrocyte-Based Biomimetic Smart Drug Delivery System as a Therapeutic and Diagnostic Tool in Cancer Therapy

by Shamama Javed, Sultan Alshehri, Ambreen Shoaib, Waquar Ahsan, Muhammad Hadi Sultan, Saad Saeed Alqahtani, Mohsin Kazi and Faiyaz Shakeel

Pharmaceutics 2021, 13(3), 368; https://doi.org/10.3390/pharmaceutics13030368 - 10 Mar 2021

Cited by 22 | Viewed by 4064

Abstract

Recently, drug delivery using natural biological carriers has emerged as one of the most widely investigated topics of research. Erythrocytes, or red blood cells, can act as potential carriers for a wide variety of drugs, including anticancer, antibacterial, antiviral, and anti-inflammatory, along with [...] Read more.

Recently, drug delivery using natural biological carriers has emerged as one of the most widely investigated topics of research. Erythrocytes, or red blood cells, can act as potential carriers for a wide variety of drugs, including anticancer, antibacterial, antiviral, and anti-inflammatory, along with various proteins, peptides, enzymes, and other macromolecules. The red blood cell-based nanocarrier systems, also called nanoerythrosomes, are nanovesicles poised with extraordinary features such as long blood circulation times, the ability to escape immune system, the ability to release the drug gradually, the protection of drugs from various endogenous factors, targeted and specified delivery of drugs, as well as possessing both therapeutic and diagnostic applications in various fields of biomedical sciences. Their journey over the last two decades is escalating with fast pace, ranging from in vivo to preclinical and clinical studies by encapsulating a number of drugs into these carriers. Being biomimetic nanoparticles, they have enhanced the stability profile of drugs and their excellent site-specific targeting ability makes them potential carrier systems in the diagnosis and therapy of wide variety of tumors including gliomas, lung cancers, breast cancers, colon cancers, gastric cancers, and other solid tumors. This review focuses on the most recent advancements in the field of nanoerythrosomes, as an excellent and promising nanoplatform for the novel drug delivery of various drugs particularly antineoplastic drugs along with their potential as a promising diagnostic tool for the identification of different tumors. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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33 pages, 7573 KiB

Open AccessReview

Inorganic Nanoparticles Applied for Active Targeted Photodynamic Therapy of Breast Cancer

by Hanieh Montaseri, Cherie Ann Kruger and Heidi Abrahamse

Pharmaceutics 2021, 13(3), 296; https://doi.org/10.3390/pharmaceutics13030296 - 24 Feb 2021

Cited by 61 | Viewed by 4964

Abstract

Photodynamic therapy (PDT) is an alternative modality to conventional cancer treatment, whereby a specific wavelength of light is applied to a targeted tumor, which has either a photosensitizer or photochemotherapeutic agent localized within it. This light activates the photosensitizer in the presence of [...] Read more.

Photodynamic therapy (PDT) is an alternative modality to conventional cancer treatment, whereby a specific wavelength of light is applied to a targeted tumor, which has either a photosensitizer or photochemotherapeutic agent localized within it. This light activates the photosensitizer in the presence of molecular oxygen to produce phototoxic species, which in turn obliterate cancer cells. The incidence rate of breast cancer (BC) is regularly growing among women, which are currently being treated with methods, such as chemotherapy, radiotherapy, and surgery. These conventional treatment methods are invasive and often produce unwanted side effects, whereas PDT is more specific and localized method of cancer treatment. The utilization of nanoparticles in PDT has shown great advantages compared to free photosensitizers in terms of solubility, early degradation, and biodistribution, as well as far more effective intercellular penetration and uptake in targeted cancer cells. This review gives an overview of the use of inorganic nanoparticles (NPs), including: gold, magnetic, carbon-based, ceramic, and up-conversion NPs, as well as quantum dots in PDT over the last 10 years (2009 to 2019), with a particular focus on the active targeting strategies for the PDT treatment of BC. Full article

(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

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