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17 pages, 5244 KiB

Open AccessArticle

In Vitro and In Vivo Effects of the Combination of Polypurine Reverse Hoogsteen Hairpins against HER-2 and Trastuzumab in Breast Cancer Cells

by Ester López-Aguilar, Patricia Fernández-Nogueira, Gemma Fuster, Neus Carbó, Carlos J. Ciudad and Véronique Noé

Int. J. Mol. Sci. 2023, 24(8), 7073; https://doi.org/10.3390/ijms24087073 - 11 Apr 2023

Viewed by 1683

Abstract

Therapeutic oligonucleotides are powerful tools for the inhibition of potential targets involved in cancer. We describe the effect of two Polypurine Reverse Hoogsteen (PPRH) hairpins directed against the ERBB2 gene, which is overexpressed in positive HER-2 breast tumors. The inhibition of their target [...] Read more.

Therapeutic oligonucleotides are powerful tools for the inhibition of potential targets involved in cancer. We describe the effect of two Polypurine Reverse Hoogsteen (PPRH) hairpins directed against the ERBB2 gene, which is overexpressed in positive HER-2 breast tumors. The inhibition of their target was analyzed by cell viability and at the mRNA and protein levels. The combination of these specific PPRHs with trastuzumab was also explored in breast cancer cell lines, both in vitro and in vivo. PPRHs designed against two intronic sequences of the ERBB2 gene decreased the viability of SKBR-3 and MDA-MB-453 breast cancer cells. The decrease in cell viability was associated with a reduction in ERBB2 mRNA and protein levels. In combination with trastuzumab, PPRHs showed a synergic effect in vitro and reduced tumor growth in vivo. These results represent the preclinical proof of concept of PPRHs as a therapeutic tool for breast cancer. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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16 pages, 4483 KiB

Open AccessArticle

Nanosecond PEF Induces Oxidative Stress and Apoptosis via Proteasomal Activity Inhibition in Gastric Adenocarcinoma Cells with Drug Resistance

by Julita Kulbacka, Nina Rembiałkowska, Anna Szewczyk, Joanna Rossowska, Małgorzata Drąg-Zalesińska, Marek Kulbacki and Anna Choromańska

Int. J. Mol. Sci. 2022, 23(21), 12943; https://doi.org/10.3390/ijms232112943 - 26 Oct 2022

Cited by 3 | Viewed by 1444

Abstract

Nanosecond (ns) pulsed electric field (PEF) is a technology in which the application of ultra-short electrical pulses can be used to disrupt the barrier function of cell plasma and internal membranes. Disruptions of the membrane integrity cause a substantial imbalance in cell homeostasis [...] Read more.

Nanosecond (ns) pulsed electric field (PEF) is a technology in which the application of ultra-short electrical pulses can be used to disrupt the barrier function of cell plasma and internal membranes. Disruptions of the membrane integrity cause a substantial imbalance in cell homeostasis in which oxidative stress is a principal component. In the present study, nsPEF-induced oxidative stress was investigated in two gastric adenocarcinoma cell lines (EPG85-257P and EPG85-257RDB) which differ by their sensitivity to daunorubicin. Cells were exposed to 200 pulses of 10 ns duration, with the amplitude and pulse repetition frequency at 1 kHz, with electric field intensity varying from 12.5 to 50 kV/cm. The electroporation buffer contained either 1 mM or 2 mM calcium chloride. CellMask DeepRed visualized cell plasma permeabilization, Fluo-4 was used to visualize internal calcium ions content, and F-actin was labeled with AlexaFluor^®488 for the cytoskeleton. The cellular viability was determined by MTT assay. An alkaline and neutral comet assay was employed to detect apoptotic and necrotic cell death. The luminescent method estimated the modifications in GSSG/GSH redox potential and the imbalance of proteasomal activity (chymotrypsin-, trypsin- and caspase-like). The reactive oxygen species (ROS) level was measured by flow cytometry using dihydroethidium (DHE) dye. Morphological visualization indicated cell shrinkage, affected cell membranes (characteristic bubbles and changed cell shape), and the reorganization of actin fibers with sites of its dense concentration; the effect was more intense with the increasing electric field strength. The most significant decrease in cell viability and GSSG/GSH redox potential was noted at the highest amplitude of 50 kV/cm, and calcium ions amplified this effect. nsPEF, particularly with calcium ions, inhibited proteasomal activities, resulting in increased protein degradation. nsPEF increased the percentage of apoptotic cells and ROS levels. The EPG85-257 RDB cell line, which is resistant to standard chemotherapy, was more sensitive to applied nsPEF protocols. The applied nsPEF method disrupted the metabolism of cancer cells and induced apoptotic cell death. The nsPEF ability to cause apoptosis, oxidative stress, and protein degradation make the nsPEF methodology a suitable alternative to current anticancer pharmacological methods. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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28 pages, 8699 KiB

Open AccessArticle

Analysis of Circulating Tumor and Cancer Stem Cells Provides New Opportunities in Diagnosis and Treatment of Small Cell Lung Cancer

by Evgenii G. Skurikhin, Natalia Ermakova, Mariia Zhukova, Olga Pershina, Edgar Pan, Angelina Pakhomova, Lena Kogai, Victor Goldberg, Elena Simolina, Victoria Skurikhina, Darius Widera, Aslan Kubatiev, Sergey G. Morozov, Nikolai Kushlinskii and Alexander Dygai

Int. J. Mol. Sci. 2022, 23(18), 10853; https://doi.org/10.3390/ijms231810853 - 17 Sep 2022

Cited by 1 | Viewed by 2446

Abstract

Current methods for diagnosis and treatment of small cell lung cancer (SCLC) have only a modest efficacy. In this pilot study, we analyzed circulating tumor cells (CTCs) and cancer stem cells (CSCs) in patients with SCLC to search for new diagnostic and prognostic [...] Read more.

Current methods for diagnosis and treatment of small cell lung cancer (SCLC) have only a modest efficacy. In this pilot study, we analyzed circulating tumor cells (CTCs) and cancer stem cells (CSCs) in patients with SCLC to search for new diagnostic and prognostic markers and novel approaches to improve the treatment of the disease. In other forms of lung cancer, we showed a heterogeneity of blood CTCs and CSCs populations, as well as changes in other cell populations (ALDH⁺, CD87⁺CD276⁺, and EGF⁺Axl⁺) in smokers. A number of CTCs and CSCs in patients with SCLC have been shown to be resistant to chemotherapy (CT). High cytotoxic activity and resistance to apoptosis of reprogrammed CD3⁺CD8⁺ T-lymphocytes (rTcells) in relation to naive CD3⁺CD8⁺ T-lymphocytes was demonstrated in a smoking patient with SCLC (Patient G) in vitro. The target for rTcells was patient G’s blood CSCs. Reprogramming of CD3⁺CD8⁺ T-lymphocytes was carried out with the MEK1/2 inhibitor and PD-1/PD-L1 pathway blocker nivolumab. The training procedure was performed with a suspension of dead CTCs and CSCs obtained from patient’s G blood. The presented data show a new avenue for personalized SCLC diagnosis and targeted improvement of chemotherapy based on the use of both CTCs and CSCs. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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14 pages, 2853 KiB

Open AccessArticle

High-Intensity Pulsed Electromagnetic Field-Mediated Gene Electrotransfection In Vitro

by Matej Kranjc, Janja Dermol-Černe, Tjaša Potočnik, Vitalij Novickij and Damijan Miklavčič

Int. J. Mol. Sci. 2022, 23(17), 9543; https://doi.org/10.3390/ijms23179543 - 23 Aug 2022

Cited by 3 | Viewed by 1811

Abstract

A high-intensity pulsed electromagnetic field (HI-PEMF) is a non-invasive and non-contact delivery method and may, as such, have an advantage over gene electrotransfer mediated by conventional electroporation using contact electrodes. Due to the limited number of in vitro studies in the field of [...] Read more.

A high-intensity pulsed electromagnetic field (HI-PEMF) is a non-invasive and non-contact delivery method and may, as such, have an advantage over gene electrotransfer mediated by conventional electroporation using contact electrodes. Due to the limited number of in vitro studies in the field of gene electrotransfection by HI-PEMF, we designed experiments to investigate and demonstrate the feasibility of such a technique for the non-viral delivery of genetic material into cells in vitro. We first showed that HI-PEMF causes DNA adsorption to the membrane, a generally accepted prerequisite step for successful gene electrotransfection. We also showed that HI-PEMF can induce gene electrotransfection as the application of HI-PEMF increased the percentage of GFP-positive cells for two different combinations of pDNA size and concentration. Furthermore, by measuring the uptake of larger molecules, i.e., fluorescently labelled dextrans of three different sizes, we showed endocytosis to be a possible mechanism for introducing large molecules into cells by HI-PEMF. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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Review

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15 pages, 1448 KiB

Open AccessReview

Extracellular Vesicles as Drug Transporters

by Monika Nowak, Julia Górczyńska, Katarzyna Kołodzińska, Jakub Rubin and Anna Choromańska

Int. J. Mol. Sci. 2023, 24(12), 10267; https://doi.org/10.3390/ijms241210267 - 17 Jun 2023

Cited by 4 | Viewed by 1973

Abstract

Extracellular vesicles (EVs) are lipid bilayer-delimited particles. According to their size and synthesis pathway, EVs can be classified into exosomes, ectosomes (microvesicles), and apoptotic bodies. Extracellular vesicles are of great interest to the scientific community due to their role in cell-to-cell communication and [...] Read more.

Extracellular vesicles (EVs) are lipid bilayer-delimited particles. According to their size and synthesis pathway, EVs can be classified into exosomes, ectosomes (microvesicles), and apoptotic bodies. Extracellular vesicles are of great interest to the scientific community due to their role in cell-to-cell communication and their drug-carrying abilities. The study aims to show opportunities for the application of EVs as drug transporters by considering techniques applicable for loading EVs, current limitations, and the uniqueness of this idea compared to other drug transporters. In addition, EVs have therapeutic potential in anticancer therapy (especially in glioblastoma, pancreatic cancer, and breast cancer). Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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19 pages, 494 KiB

Open AccessReview

Irreversible Electroporation in Pancreatic Cancer—An Evolving Experimental and Clinical Method

by Agnieszka Gajewska-Naryniecka, Urszula Szwedowicz, Zofia Łapińska, Julia Rudno-Rudzińska, Wojciech Kielan and Julita Kulbacka

Int. J. Mol. Sci. 2023, 24(5), 4381; https://doi.org/10.3390/ijms24054381 - 23 Feb 2023

Cited by 5 | Viewed by 3132

Abstract

Pancreatic cancer has no symptoms until the disease has advanced and is aggressive cancer with early metastasis. Up to now, the only curative treatment is surgical resection, which is possible in the early stages of the disease. Irreversible electroporation treatment offers new hope [...] Read more.

Pancreatic cancer has no symptoms until the disease has advanced and is aggressive cancer with early metastasis. Up to now, the only curative treatment is surgical resection, which is possible in the early stages of the disease. Irreversible electroporation treatment offers new hope for patients with unresectable tumors. Irreversible electroporation (IRE) is a type of ablation therapy that has been explored as a potential treatment for pancreatic cancer. Ablation therapies involve the use of energy to destroy or damage cancer cells. IRE involves using high-voltage, low-energy electrical pulses to create resealing in the cell membrane, causing the cell to die. This review summarizes experiential and clinical findings in terms of the IRE applications. As was described, IRE can be a non-pharmacological approach (electroporation) or combined with anticancer drugs or standard treatment methods. The efficacy of irreversible electroporation (IRE) in eliminating pancreatic cancer cells has been demonstrated through both in vitro and in vivo studies, and it has been shown to induce an immune response. Nevertheless, further investigation is required to assess its effectiveness in human subjects and to comprehensively understand IRE’s potential as a treatment option for pancreatic cancer. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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15 pages, 584 KiB

Open AccessReview

Progress in Anticancer Drug Development Targeting Ubiquitination-Related Factors

by Qianqian Li and Weiwei Zhang

Int. J. Mol. Sci. 2022, 23(23), 15104; https://doi.org/10.3390/ijms232315104 - 01 Dec 2022

Cited by 5 | Viewed by 1588

Abstract

Ubiquitination is extensively involved in critical signaling pathways through monitoring protein stability, subcellular localization, and activity. Dysregulation of this process results in severe diseases including malignant cancers. To develop drugs targeting ubiquitination-related factors is a hotspot in research to realize better therapy of [...] Read more.

Ubiquitination is extensively involved in critical signaling pathways through monitoring protein stability, subcellular localization, and activity. Dysregulation of this process results in severe diseases including malignant cancers. To develop drugs targeting ubiquitination-related factors is a hotspot in research to realize better therapy of human diseases. Ubiquitination comprises three successive reactions mediated by Ub-activating enzyme E1, Ub-conjugating enzyme E2, and Ub ligase E3. As expected, multiple ubiquitination enzymes have been highlighted as targets for anticancer drug development due to their dominant effect on tumorigenesis and cancer progression. In this review, we discuss recent progresses in anticancer drug development targeting enzymatic machinery components. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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15 pages, 3510 KiB

Open AccessReview

Topical Delivery of Hedgehog Inhibitors: Current Status and Perspectives

by Kristian Kåber Pedersen, Maria Helena Høyer-Hansen, Thomas Litman, Merete Hædersdal and Uffe Høgh Olesen

Int. J. Mol. Sci. 2022, 23(22), 14191; https://doi.org/10.3390/ijms232214191 - 16 Nov 2022

Cited by 3 | Viewed by 1722

Abstract

Systemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tumor [...] Read more.

Systemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tumor tissue. The aim of this review was to evaluate the current status of topical HHi delivery for BCCs and discuss barriers for translating systemic HHis into topical treatments. A literature search identified 16 preclinical studies and 7 clinical trials on the topical delivery of 12 HHis that have been clinically tested on BCCs. Preclinical studies on drug uptake demonstrated that novel formulations, and delivery- and pre-treatment techniques enhanced topical HHi delivery. Murine studies showed that the topical delivery of sonidegib, itraconazole, vitamin D₃ and CUR-61414 led to biological responses and tumor remission. In clinical trials, only topical patidegib and sonidegib led to at least a partial response in 26/86 BCCs and 30/34 patients, respectively. However, histological clearance was not observed in the samples analyzed. In conclusion, the incomplete clinical response could be due to poor HHi uptake, biodistribution or biological response over time. Novel topical delivery techniques may improve HHi delivery, but additional research on cutaneous pharmacokinetics and biological response is needed. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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18 pages, 1691 KiB

Open AccessReview

Integrin Alpha v Beta 6 (αvβ6) and Its Implications in Cancer Treatment

by Ewa Brzozowska and Sameer Deshmukh

Int. J. Mol. Sci. 2022, 23(20), 12346; https://doi.org/10.3390/ijms232012346 - 15 Oct 2022

Cited by 7 | Viewed by 5081

Abstract

Integrins are necessary for cell adhesion, migration, and positioning. Essential for inducing signalling events for cell survival, proliferation, and differentiation, they also trigger a variety of signal transduction pathways involved in mediating invasion, metastasis, and squamous-cell carcinoma. Several recent studies have demonstrated that [...] Read more.

Integrins are necessary for cell adhesion, migration, and positioning. Essential for inducing signalling events for cell survival, proliferation, and differentiation, they also trigger a variety of signal transduction pathways involved in mediating invasion, metastasis, and squamous-cell carcinoma. Several recent studies have demonstrated that the up- and down-regulation of the expression of αv and other integrins can be a potent marker of malignant diseases and patient prognosis. This review focuses on an arginine-glycine-aspartic acid (RGD)-dependent integrin αVβ6, its biology, and its role in healthy humans. We examine the implications of αVβ6 in cancer progression and the promotion of epithelial-mesenchymal transition (EMT) by contributing to the activation of transforming growth factor beta TGF-β. Although αvβ6 is crucial for proper function in healthy people, it has also been validated as a target for cancer treatment. This review briefly considers aspects of targeting αVβ6 in the clinic via different therapeutic modalities. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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29 pages, 1823 KiB

Open AccessReview

Landscape of Cellular Bioeffects Triggered by Ultrasound-Induced Sonoporation

by Dawid Przystupski and Marek Ussowicz

Int. J. Mol. Sci. 2022, 23(19), 11222; https://doi.org/10.3390/ijms231911222 - 23 Sep 2022

Cited by 11 | Viewed by 2773

Abstract

Sonoporation is the process of transient pore formation in the cell membrane triggered by ultrasound (US). Numerous studies have provided us with firm evidence that sonoporation may assist cancer treatment through effective drug and gene delivery. However, there is a massive gap in [...] Read more.

Sonoporation is the process of transient pore formation in the cell membrane triggered by ultrasound (US). Numerous studies have provided us with firm evidence that sonoporation may assist cancer treatment through effective drug and gene delivery. However, there is a massive gap in the body of literature on the issue of understanding the complexity of biophysical and biochemical sonoporation-induced cellular effects. This study provides a detailed explanation of the US-triggered bioeffects, in particular, cell compartments and the internal environment of the cell, as well as the further consequences on cell reproduction and growth. Moreover, a detailed biophysical insight into US-provoked pore formation is presented. This study is expected to review the knowledge of cellular effects initiated by US-induced sonoporation and summarize the attempts at clinical implementation. Full article

(This article belongs to the Special Issue Targeted Therapies and Molecular Methods in Cancer)

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