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Drug Repurposing for Cancer Therapies
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Drug Repurposing for Cancer Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 17360

Special Issue Editors

Dr. Cristina P.R. Xavier

E-Mail Website
Guest Editor
i3S—Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
Interests: cancer drug resistance; extracellular vesicles (EVs) as mediators of cancer drug resistance; anticancer activity of compounds (of natural or chemical origin); impact of the tumor microenvironment on cancer drug resistance; molecular mechanisms for overcoming drug resistance; apoptosis; cancer cell proliferation
Special Issues, Collections and Topics in MDPI journals
Dr. Andreia Palmeira

E-Mail Website
Guest Editor
1. Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
2. Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, s/n, 4450-208 Matosinhos, Portugal
Interests: medicinal and pharmaceutical chemistry; computational chemistry; structure and ligand-based computer-assisted drug design

Special Issue Information

Dear Colleagues,

Cancer therapy remains a major challenge particularly in cancers resistance to therapy. New and more effective therapeutic strategies are needed to improve cancer treatment. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of their original clinical indication. This approach has been emerging as an interesting alternative to the conventional drug discovery process. In recent years, several studies have investigated the potential of drug repurposing candidates for cancer treatment, either as single agents or in combination with approved cancer therapy, by targeting multiple hallmarks of cancer. This Special Issue aims to collect original research articles studying drugs previously approved for diseases other than cancer, with impact on cancer treatment. Review artcicles will be also considered.

Dr. Cristina P.R. Xavier
Dr. Andreia Palmeira
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • repurposed drugs
  • cancer therapy
  • anticancer drugs
  • cancer drug resistance
  • pharmacology
  • therapeutic strategies
  • combination of drugs to improve cancer treatment

Published Papers (7 papers)

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Editorial

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3 pages, 172 KiB  
Editorial
Special Issue: “Drug Repurposing for Cancer Therapies”
by Cristina P. R. Xavier and Andreia Palmeira
Int. J. Mol. Sci. 2024, 25(2), 1092; https://doi.org/10.3390/ijms25021092 - 16 Jan 2024
Viewed by 923
Abstract
Cancer is one of the primary global causes of death, thus addressing cancer therapy remains a significant challenge, especially in cases where cancers exhibit resistance to treatment [...] Full article
(This article belongs to the Special Issue Drug Repurposing for Cancer Therapies)

Research

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27 pages, 15492 KiB  
Article
Combined Inhibition of UBE2C and PLK1 Reduce Cell Proliferation and Arrest Cell Cycle by Affecting ACLY in Pan-Cancer
by Keying Liang, Qian Wang, Li Qiu, Xiaocheng Gong, Zixi Chen, Haibo Zhang, Ke Ding, Yunfei Liu, Jinfen Wei, Shudai Lin, Shuying Fu and Hongli Du
Int. J. Mol. Sci. 2023, 24(21), 15658; https://doi.org/10.3390/ijms242115658 - 27 Oct 2023
Cited by 2 | Viewed by 1623
Abstract
Various studies have shown that the cell-cycle-related regulatory proteins UBE2C, PLK1, and BIRC5 promote cell proliferation and migration in different types of cancer. However, there is a lack of in-depth and systematic research on the mechanism of these three as therapeutic targets. In [...] Read more.
Various studies have shown that the cell-cycle-related regulatory proteins UBE2C, PLK1, and BIRC5 promote cell proliferation and migration in different types of cancer. However, there is a lack of in-depth and systematic research on the mechanism of these three as therapeutic targets. In this study, we found a positive correlation between the expression of UBE2C and PLK1/BIRC5 in the Cancer Genome Atlas (TCGA) database, revealing a potential combination therapy candidate for pan-cancer. Quantitative real-time PCR (qRT-PCR), Western blotting (WB), cell phenotype detection, and RNA-seq techniques were used to evidence the effectiveness of the combination candidate. We found that combined interference of UBE2C with PLK1 and UBE2C with BIRC5 affected metabolic pathways by significantly downregulating the mRNA expression of IDH1 and ACLY, which was related to the synthesis of acetyl-CoA. By combining the PLK1 inhibitor volasertib and the ACLY inhibitor bempedoic acid, it showed a higher synergistic inhibition of cell viability and higher synergy scores in seven cell lines, compared with those of other combination treatments. Our study reveals the potential mechanisms through which cell-cycle-related genes regulate metabolism and proposes a potential combined targeted therapy for patients with higher PLK1 and ACLY expression in pan-cancer. Full article
(This article belongs to the Special Issue Drug Repurposing for Cancer Therapies)
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17 pages, 3982 KiB  
Article
Mitochondrial Dysfunction Involved in the Cytotoxicity of Tramadol in Human Endometrial Carcinoma Cells
by Li-Chun Liu, Zih-Syuan Wu, Jia-Lin Chen, Zhi-Fu Wu, Hou-Chuan Lai and Yi-Hsuan Huang
Int. J. Mol. Sci. 2023, 24(1), 99; https://doi.org/10.3390/ijms24010099 - 21 Dec 2022
Cited by 6 | Viewed by 2025
Abstract
Tramadol is a common anesthetic used to treat cancer pain, including endometrial cancer, but its function in endometrial cancer remains unclear. The purpose of this study was to elucidate the antitumor effects of tramadol on human endometrial cancer cells. Colony formation, BrdU, cell [...] Read more.
Tramadol is a common anesthetic used to treat cancer pain, including endometrial cancer, but its function in endometrial cancer remains unclear. The purpose of this study was to elucidate the antitumor effects of tramadol on human endometrial cancer cells. Colony formation, BrdU, cell cycle profiles, apoptosis, ROS, and Western blot analyses were used to study the response of endometrial cancer cells to tramadol. JC-1 and seahorse metabolic flux assays were used to detect the effect of tramadol on mitochondria in endometrial cancer cells. Combination index was used to detect the interaction of tramadol with chemotherapy drugs in endometrial cancer cells. In this study, we found that tramadol was able to inhibit proliferation and induce cell cycle arrest, ROS generation, and apoptosis in two types of endometrial cancer cells. In addition, tramadol treatment also induced mitochondrial dysfunction in endometrial cancer cells by causing a loss of mitochondrial membrane potential and a decreased oxygen consumption rate. More importantly, the synergetic effect of tramadol with doxorubicin or cisplatin was further confirmed in endometrial cancer cells by the results of the combination index and apoptosis assay. In summary, our findings indicate that tramadol has an antitumor effect on endometrial cancer cells, which might serve as a potential adjuvant therapy strategy for endometrial cancer. Full article
(This article belongs to the Special Issue Drug Repurposing for Cancer Therapies)
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Graphical abstract

14 pages, 3128 KiB  
Article
Disulfiram/Copper Suppresses Cancer Stem Cell Activity in Differentiated Thyroid Cancer Cells by Inhibiting BMI1 Expression
by Yung-Lun Ni, Peng-Ju Chien, Hung-Chia Hsieh, Huan-Ting Shen, Hsueh-Te Lee, Shih-Ming Chen and Wen-Wei Chang
Int. J. Mol. Sci. 2022, 23(21), 13276; https://doi.org/10.3390/ijms232113276 - 31 Oct 2022
Cited by 10 | Viewed by 2169
Abstract
Differentiated thyroid carcinomas (DTCs), which have papillary and follicular types, are common endocrine malignancies worldwide. Cancer stem cells (CSCs) are a particular type of cancer cells within bulk tumors involved in cancer initiation, drug resistance, and metastasis. Cells with high intracellular aldehyde hydrogenase [...] Read more.
Differentiated thyroid carcinomas (DTCs), which have papillary and follicular types, are common endocrine malignancies worldwide. Cancer stem cells (CSCs) are a particular type of cancer cells within bulk tumors involved in cancer initiation, drug resistance, and metastasis. Cells with high intracellular aldehyde hydrogenase (ALDH) activity are a population of CSCs in DTCs. Disulfiram (DSF), an ALDH inhibitor used for the treatment of alcoholism, reportedly targets CSCs in various cancers when combined with copper. This study reported for the first time that DSF/copper can inhibit the proliferation of papillary and follicular DTC lines. DSF/copper suppressed thyrosphere formation, indicating the inhibition of CSC activity. Molecular mechanisms of DSF/copper involved downregulating the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1) and cell cycle-related proteins, including cyclin B2, cyclin-dependent kinase (CDK) 2, and CDK4, in a dose-dependent manner. BMI1 overexpression diminished the inhibitory effect of DSF/copper in the thyrosphere formation of DTC cells. BMI1 knockdown by RNA interference in DTC cells also suppressed the self-renewal capability. DSF/copper could inhibit the nuclear localization and transcriptional activity of c-Myc and the binding of E2F1 to the BMI1 promoter. Overexpression of c-Myc or E2F1 further abolished the inhibitory effect of DSF/copper on BMI1 expression, suggesting that the suppression of c-Myc and E2F1 by DSF/copper was involved in the downregulation of BMI1 expression. In conclusion, DSF/copper targets CSCs in DTCs by inhibiting c-Myc- or E2F1-mediated BMI1 expression. Therefore, DSF is a potential therapeutic agent for future therapy in DTCs. Full article
(This article belongs to the Special Issue Drug Repurposing for Cancer Therapies)
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21 pages, 5275 KiB  
Article
Exploring Amodiaquine’s Repurposing Potential in Breast Cancer Treatment—Assessment of In-Vitro Efficacy & Mechanism of Action
by Vineela Parvathaneni, Rameswari Chilamakuri, Nishant S. Kulkarni, Nabeela F. Baig, Saurabh Agarwal and Vivek Gupta
Int. J. Mol. Sci. 2022, 23(19), 11455; https://doi.org/10.3390/ijms231911455 - 28 Sep 2022
Cited by 4 | Viewed by 2255
Abstract
Due to the heterogeneity of breast cancer, current available treatment options are moderately effective at best. Hence, it is highly recommended to comprehend different subtypes, understand pathogenic mechanisms involved, and develop treatment modalities. The repurposing of an old FDA approved anti-malarial drug, amodiaquine [...] Read more.
Due to the heterogeneity of breast cancer, current available treatment options are moderately effective at best. Hence, it is highly recommended to comprehend different subtypes, understand pathogenic mechanisms involved, and develop treatment modalities. The repurposing of an old FDA approved anti-malarial drug, amodiaquine (AQ) presents an outstanding opportunity to explore its efficacy in treating majority of breast cancer subtypes. Cytotoxicity, scratch assay, vasculogenic mimicry study, and clonogenic assay were employed to determine AQ’s ability to inhibit cell viability, cell migration, vascular formation, and colony growth. 3D Spheroid cell culture studies were performed to identify tumor growth inhibition potential of AQ in MCF-7 and MDAMB-231 cell lines. Apoptosis assays, cell cycle analysis, RT-qPCR assays, and Western blot studies were performed to determine AQ’s ability to induce apoptosis, cell cycle changes, gene expression changes, and induction of autophagy marker proteins. The results from in-vitro studies confirmed the potential of AQ as an anti-cancer drug. In different breast cancer cell lines tested, AQ significantly induces cytotoxicity, inhibit colony formation, inhibit cell migration, reduces 3D spheroid volume, induces apoptosis, blocks cell cycle progression, inhibit expression of cancer related genes, and induces LC3BII protein to inhibit autophagy. Our results demonstrate that amodiaquine is a promising drug to repurpose for breast cancer treatment, which needs numerous efforts from further studies. Full article
(This article belongs to the Special Issue Drug Repurposing for Cancer Therapies)
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16 pages, 2379 KiB  
Article
Pirfenidone Sensitizes NCI-H460 Non-Small Cell Lung Cancer Cells to Paclitaxel and to a Combination of Paclitaxel with Carboplatin
by Helena Branco, Júlio Oliveira, Catarina Antunes, Lúcio L. Santos, Maria Helena Vasconcelos and Cristina P. R. Xavier
Int. J. Mol. Sci. 2022, 23(7), 3631; https://doi.org/10.3390/ijms23073631 - 26 Mar 2022
Cited by 12 | Viewed by 3210
Abstract
Pirfenidone, an antifibrotic drug, has antitumor potential against different types of cancers. Our work explored whether pirfenidone sensitizes non-small cell lung cancer (NSCLC) cell lines to chemotherapeutic treatments. The cytotoxic effect of paclitaxel in combination with pirfenidone against three NSCLC cell lines (A549, [...] Read more.
Pirfenidone, an antifibrotic drug, has antitumor potential against different types of cancers. Our work explored whether pirfenidone sensitizes non-small cell lung cancer (NSCLC) cell lines to chemotherapeutic treatments. The cytotoxic effect of paclitaxel in combination with pirfenidone against three NSCLC cell lines (A549, NCI-H322 and NCI-H460) was evaluated using the sulforhodamine B assay. The effects of this combination on cell viability (trypan blue exclusion assay), proliferation (BrdU incorporation assay), cell cycle (flow cytometry following PI staining) and cell death (Annexin V-FITC detection assay and Western blot) were analyzed on the most sensitive cell line (NCI-H460). The cytotoxic effect of this drug combination was also evaluated against two non-tumorigenic cell lines (MCF-10A and MCF-12A). Finally, the ability of pirfenidone to sensitize NCI-H460 cells to a combination of paclitaxel plus carboplatin was assessed. The results demonstrated that pirfenidone sensitized NCI-H460 cells to paclitaxel treatment, reducing cell growth, viability and proliferation, inducing alterations in the cell cycle profile and causing an increase in the % of cell death. Remarkably, this combination did not increase cytotoxicity in non-tumorigenic cells. Importantly, pirfenidone also sensitized NCI-H460 cells to paclitaxel plus carboplatin. This work highlights the possibility of repurposing pirfenidone in combination with chemotherapy for the treatment of NSCLC. Full article
(This article belongs to the Special Issue Drug Repurposing for Cancer Therapies)
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Review

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14 pages, 924 KiB  
Review
Drug Repurposing in Cancer Therapy: Influence of Patient’s Genetic Background in Breast Cancer Treatment
by Rafaela Rodrigues, Diana Duarte and Nuno Vale
Int. J. Mol. Sci. 2022, 23(8), 4280; https://doi.org/10.3390/ijms23084280 - 14 Apr 2022
Cited by 30 | Viewed by 3906
Abstract
Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type [...] Read more.
Cancer is among the leading causes of death worldwide and it is estimated that in 2040 more than 29 million people will be diagnosed with some type of cancer. The most prevalent type of cancer in women, worldwide, is breast cancer, a type of cancer associated with a huge death rate. This high mortality is mainly a consequence of the development of drug resistance, which is one of the major challenges to overcome in breast cancer treatment. As a result, research has been focused on finding novel therapeutical weapons, specifically ones that allow for a personalized treatment, based on patients’ characteristics. Although the scientific community has been concerned about guaranteeing the quality of life of cancer patients, researchers are also aware of the increasing costs related to cancer treatment, and efforts have been made to find alternatives to the development of new drugs. The development of new drugs presents some disadvantages as it is a multistep process that is time- and money-consuming, involving clinical trials that commonly fail in the initial phases. A strategy to overcome these disadvantages is drug repurposing. In this review, we focused on describing potential repurposed drugs in the therapy of breast cancer, considering their pharmacogenomic profile, to assess the relationship between patients’ genetic variations and their response to a certain therapy. This review supports the need for the development of further fundamental studies in this area, in order to investigate and expand the knowledge of the currently used and novel potential drugs to treat breast cancer. Future clinical trials should focus on developing strategies to group cancer patients according to their clinical and biological similarities and to discover new potential targets, to enable cancer therapy to be more effective and personalized. Full article
(This article belongs to the Special Issue Drug Repurposing for Cancer Therapies)
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