Current and Future Cancer Chemoprevention Strategies, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (20 May 2024) | Viewed by 10592

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Department of Molecular Oncology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11129 Belgrade, Serbia
Interests: oncology; tumor progression; chemotherapy; inflammation; cellular senescence
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Molecular Biology Laboratory, Faculty of Medicine, University of Atacama, Atacama, Chile
Interests: biologia molecular; fisiopatologia
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Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
Interests: cancer metabolism; mTORC1 signaling; glutamine metabolism; hepatocellular carcinoma
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Special Issue Information

Dear Colleagues,

We are pleased to announce the new Special Issue for Pharmaceutics entitled "Current and Future Cancer Chemoprevention Strategies, Volume II."

The increasing understanding of cancer pathobiology has shown how to develop molecular approaches to treating neoplasm and decreasing mortality rates. These advances have also influenced active chemoprevention development to promote cancer prevention and development, reduce cancer incidence or counter disease progression, and cancer recurrence after surgery.

Chemoprevention includes the use of natural, synthetic, or biological agents with the aim, at a molecular level, to reverse, suppress, or prevent either the initial phases of carcinogenesis or the progression of premalignant cells to the invasive disease stage. Understanding chemopreventive agents' molecular mechanisms will shed light on preventing carcinogenesis and new therapeutic strategies’ compounds with potential clinical applications.

For this Special Issue on "Current and future cancer chemoprevention strategies", we encourage authors to submit their original research or review articles that bring new pieces of evidence or synthesis of the most recent and breakthrough data in the field of cancer chemoprevention. Topics include, but are not limited to: inorganic and organic compounds; nano-compounds; natural compounds; plant extracts; hormonal chemopreventive agents; diet-related agents; medication/pharmacological drugs; repurposing drugs.

Dr. Juan F. Santibanez
Dr. César A. Echeverría
Dr. Victor Hugo Villar
Guest Editors

Manuscript Submission Information

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Keywords

  • chemoprevention

  • cancer
  • cell death
  • metabolism
  • cell invasion
  • metastasis

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Published Papers (6 papers)

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Research

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23 pages, 12793 KiB  
Article
New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs
by Thalia Delgado, Denisa Veselá, Hana Dostálová, Vladimír Kryštof, Veronika Vojáčková, Radek Jorda, Alejandro Castro, Jeanluc Bertrand, Gildardo Rivera, Mario Faúndez, Miroslav Strnad, Christian Espinosa-Bustos and Cristian O. Salas
Pharmaceutics 2024, 16(5), 649; https://doi.org/10.3390/pharmaceutics16050649 - 11 May 2024
Viewed by 361
Abstract
Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. However, despite their efficacy in the treatment of CML, a mechanism of resistance to [...] Read more.
Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. However, despite their efficacy in the treatment of CML, a mechanism of resistance to these drugs associated with mutations in the kinase region has emerged. Therefore, in this work, we report the synthesis of 14 new 2,6,9-trisubstituted purines designed from our previous Bcr-Abl inhibitors. Here, we highlight 11b, which showed higher potency against Bcr-Abl (IC50 = 0.015 μM) than imatinib and nilotinib and exerted the most potent antiproliferative properties on three CML cells harboring the Bcr-Abl rearrangement (GI50 = 0.7–1.3 μM). In addition, these purines were able to inhibit the growth of KCL22 cell lines expressing Bcr-AblT315I, Bcr-AblE255K, and Bcr-AblY253H point mutants in micromolar concentrations. Imatinib and nilotinib were ineffective in inhibiting the growth of KCL22 cells expressing Bcr-AblT315I (GI50 > 20 μM) compared to 11bf (GI50 = 6.4–11.5 μM). Molecular docking studies explained the structure–activity relationship of these purines in Bcr-AblWT and Bcr-AblT315I. Finally, cell cycle cytometry assays and immunodetection showed that 11b arrested the cells in G1 phase, and that 11b downregulated the protein levels downstream of Bcr-Abl in these cells. Full article
(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies, 2nd Edition)
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15 pages, 3592 KiB  
Article
Antimetastatic Properties of Prodigiosin and the BH3-Mimetic Obatoclax (GX15-070) in Melanoma
by Margarita Espona-Fiedler, Pilar Manuel-Manresa, Cristina Benítez-García, Pere Fontova, Roberto Quesada, Vanessa Soto-Cerrato and Ricardo Pérez-Tomás
Pharmaceutics 2023, 15(1), 97; https://doi.org/10.3390/pharmaceutics15010097 - 28 Dec 2022
Cited by 1 | Viewed by 1759
Abstract
Metastasis is the primary cause of death in cancer patients. Many current chemotherapeutic agents only show cytotoxic, but not antimetastatic properties. This leads to a reduction in tumor size, but allows cancer cells to disseminate, which ultimately causes patient death. Therefore, novel anticancer [...] Read more.
Metastasis is the primary cause of death in cancer patients. Many current chemotherapeutic agents only show cytotoxic, but not antimetastatic properties. This leads to a reduction in tumor size, but allows cancer cells to disseminate, which ultimately causes patient death. Therefore, novel anticancer compounds with both effects need to be developed. In this work, we analyze the antimetastatic properties of prodigiosin and obatoclax (GX15-070), anticancer drugs of the Prodiginines (PGs) family. We studied PGs’ effects on cellular adhesion and morphology in the human primary and metastatic melanoma cell lines, SK-MEL-28 and SK-MEL-5, and in the murine melanoma cell line, B16F10A. Cell adhesion sharply decreased in the treated cells, and this was accompanied by a reduction in filopodia protrusions and a significant decrease in the number of focal-adhesion structures. Moreover, cell migration was assessed through the wound-healing assay and cell motility was severely inhibited after 24 h of treatment. To elucidate the molecular mechanisms involved, changes in metastasis-related genes were analyzed through a gene-expression array. Key genes related to cellular invasion, migration and chemoresistance were significantly down-regulated. Finally, an in vivo model of melanoma-induced lung metastasis was established and significant differences in lung tumors were observed in the obatoclax-treated mice. Altogether, these results describe, in depth, PGs’ cellular antimetastatic effects and identify in vivo antimetastatic properties of Obatoclax. Full article
(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies, 2nd Edition)
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19 pages, 3570 KiB  
Article
Suppressing of Src–Hic-5–JNK–AKT Signaling Reduced GAPDH Expression for Preventing the Progression of HuCCT1 Cholangiocarcinoma
by Wen-Sheng Wu, Rui-Fang Chen, Chuan-Chu Cheng, Jia-Ling Wei, Chen-Fang Lin, Ren-In You, Yen-Chang Chen, Ming-Che Lee and Yen-Cheng Chen
Pharmaceutics 2022, 14(12), 2698; https://doi.org/10.3390/pharmaceutics14122698 - 2 Dec 2022
Cited by 1 | Viewed by 1573
Abstract
Cholangiocarcinoma (CCA) is a malignant neoplasm of the bile ducts, being the second most common type of cancer in the liver, and most patients are diagnosed at a late stage with poor prognosis. Targeted therapy aiming at receptors tyrosine kinases (RTKs) such as [...] Read more.
Cholangiocarcinoma (CCA) is a malignant neoplasm of the bile ducts, being the second most common type of cancer in the liver, and most patients are diagnosed at a late stage with poor prognosis. Targeted therapy aiming at receptors tyrosine kinases (RTKs) such as c-Met or EGFR have been developed but with unsatisfactory outcomes. In our recent report, we found several oncogenic molecules downstream of RTKs, including hydrogen peroxide clone-5 (Hic-5), Src, AKT and JNK, were elevated in tissues of a significant portion of metastatic CCAs. By inhibitor studies and a knockdown approach, these molecules were found to be within the same signal cascade responsible for the migration of HuCCT1 cells, a conventionally used CCA cell line. Herein, we also found Src inhibitor dasatinib and Hic-5 siRNA corporately suppressed HuCCT1 cell invasion. Moreover, dasatinib inhibited the progression of the HuCCT1 tumor on SCID mice skin coupled with decreasing the expression of Hic-5 and EGFR and the activities of Src, AKT and JNK. In addition, we found a glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and several cytoskeletal molecules such as tubulin and cofilin were dramatically decreased after a long-term treatment of the HuCCT1 tumor with a high dose of dasatinib. Specifically, GAPDH was shown to be a downstream effector of the Hic-5/Src/AKT cascade involved in HuCCT1 cell migration. On the other hand, TFK1, another CCA cell line without Hic-5 expression, exhibited very low motility, whereas an ectopic Hic-5 expression enhanced the activation of Src and AKT and marginally increased TFK1 migration. In the future, it is tempting to investigate whether cotargeting Src, Hic-5 and/or GAPDH is efficient for preventing CCA progression in future clinical trials. Full article
(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies, 2nd Edition)
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23 pages, 5708 KiB  
Article
Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
by Dusan Ruzic, Bernhard Ellinger, Nemanja Djokovic, Juan F. Santibanez, Sheraz Gul, Milan Beljkas, Ana Djuric, Arasu Ganesan, Aleksandar Pavic, Tatjana Srdic-Rajic, Milos Petkovic and Katarina Nikolic
Pharmaceutics 2022, 14(12), 2600; https://doi.org/10.3390/pharmaceutics14122600 - 25 Nov 2022
Cited by 7 | Viewed by 2149
Abstract
Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery [...] Read more.
Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations. Full article
(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies, 2nd Edition)
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20 pages, 707 KiB  
Review
Therapeutic Implications of PTEN in Non-Small Cell Lung Cancer
by Zaid Sirhan, Rawan Alojair, Anita Thyagarajan and Ravi P. Sahu
Pharmaceutics 2023, 15(8), 2090; https://doi.org/10.3390/pharmaceutics15082090 - 5 Aug 2023
Cited by 2 | Viewed by 1628
Abstract
Lung cancer remains one of the major human malignancies affecting both men and women worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent type. Multiple mechanisms have been identified that favor tumor growth as well as impede the efficacy of therapeutic [...] Read more.
Lung cancer remains one of the major human malignancies affecting both men and women worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent type. Multiple mechanisms have been identified that favor tumor growth as well as impede the efficacy of therapeutic regimens in lung cancer patients. Among tumor suppressor genes that play critical roles in regulating cancer growth, the phosphatase and tensin homolog (PTEN) constitutes one of the important family members implicated in controlling various functional activities of tumor cells, including cell proliferation, apoptosis, angiogenesis, and metastasis. Notably, clinical studies have also documented that lung tumors having an impaired, mutated, or loss of PTEN are associated with low survival or high tumor recurrence rates. To that end, PTEN has been explored as a promising target for anti-cancer agents. Importantly, the ability of PTEN to crosstalk with several signaling pathways provides new approaches to devise effective treatment options for lung cancer treatment. The current review highlights the significance of PTEN and its implications in therapeutic approaches against NSCLC. Full article
(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies, 2nd Edition)
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16 pages, 660 KiB  
Review
Chemopreventive and Anticancer Role of Resveratrol against Oral Squamous Cell Carcinoma
by Giuseppe Angellotti, Giulia Di Prima, Elena Belfiore, Giuseppina Campisi and Viviana De Caro
Pharmaceutics 2023, 15(1), 275; https://doi.org/10.3390/pharmaceutics15010275 - 13 Jan 2023
Cited by 15 | Viewed by 2297
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most prevailing and aggressive head and neck cancers, featuring high morbidity and mortality. The available conventional treatments suffer from several adverse effects and are often inefficient in terms of their survival rates. Thus, seeking [...] Read more.
Oral squamous cell carcinoma (OSCC) is one of the most prevailing and aggressive head and neck cancers, featuring high morbidity and mortality. The available conventional treatments suffer from several adverse effects and are often inefficient in terms of their survival rates. Thus, seeking novel therapeutic agents and adjuvants is of the utmost importance for modern society. Natural polyphenolic compounds have recently emerged as promising chemopreventive and anticancer agents. Specifically, the natural compound resveratrol (RSV) has recently gained momentum for this purpose. RSV is useful for treating OSCC due to its antiproliferative, antimetastatic, and proapoptotic effects. Additionally, RSV acts against tumor cells while synergically cooperating with chemotherapeutics, overcoming drug resistance phenomena. Despite these wide-spectrum effects, there are few specific investigations regarding RSV’s effects against OSCC animal models that consider different routes and vehicles for the administration of RSV. Interestingly, an injectable RSV-loaded liposome-based formulation was proven to be effective against both in vitro and in vivo OSCC models, demonstrating that the development of RSV-loaded drug delivery systems for systemic and/or loco-regional applications may be the turning point in oral cancer treatment, leading to benefits from both RSV’s properties as well as from targeted delivery. Given these premises, this review offers a comprehensive overview of the in vitro and in vivo effects of RSV and its main derivative, polydatin (PD), against OSCC-related cell lines and animal models, aiming to guide the scientific community in regard to RSV and PD use in the treatment of oral precancerous and cancerous lesions. Full article
(This article belongs to the Special Issue Current and Future Cancer Chemoprevention Strategies, 2nd Edition)
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