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Cancers
Special Issues
Drug Repurposing and Reformulation for Cancer Treatment
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Drug Repurposing and Reformulation for Cancer Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 April 2024) | Viewed by 14637

Special Issue Editors

Dr. Abhijit Date

E-Mail Website
Guest Editor
R.K. Coit College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA
Interests: drug repurposing; nanomedicine; bladder cancer; leukemia; infectious diseases; ionic liquids
Dr. Arati Sharma

E-Mail Website
Guest Editor
Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Interests: leukemia; melanoma; target identification and validation; experimental therapeutics; animal models; preclinical drug development; translational oncology research
Prof. Dr. Dhimant Desai

E-Mail Website
Guest Editor
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
Interests: synthesis; chemopreventive agent; chemotherapeutic agent; enviromental carcinogens; in vitro and in vivo studies; leukemia; melanoma; colon cancer

Special Issue Information

Dear Colleagues,

Cancer is responsible for the second-highest number of deaths worldwide, and efforts to combat this global health problem have led to numerous discoveries, altering the paradigms of cancer therapy and improving the life expectancy of cancer patients. Despite these advances, several cancers still have poor prognoses and a dismal 5-year survival rate. The traditional drug discovery and development path is time consuming (12–15 years) and incurs exorbitant costs (~2–3 billion USD), with less than 5% of new chemical entities from drug discovery programs reaching beyond the phase I stage of clinical trials. Thus, there is a dire need for a strategy capable of minimizing the cost and duration of drug development, improving the success rate.

Drug repurposing is a drug development strategy that focuses on establishing new therapeutic indications for FDA-approved or previously discarded drugs. The availability of pharmacokinetic, tolerability and toxicological profiles of the drug considered for repurposing is a major advantage, able to accentuate the clinical translation of the repurposed drug with a concomitant reduction in the development time and cost. While drug repurposing is not new in the medical field, including cancer therapy, it received great impetus when the retrospective analysis of clinical data in cancer patients revealed that low-cost, off-patent, and FDA-approved non-oncology drugs such as metformin can be useful for cancer prevention and therapy, and the repurposing and reformulation of drugs is actively being pursued globally for the treatment of various cancers, with numerous clinical trials having been initiated to facilitate the translation of repurposed drugs for cancer therapy.

We are pleased to invite you to submit original contributions and/or reviews highlighting the potential of FDA-approved or previously discarded drugs in curbing cancer initiation, progression, and/or metastasis, and drug resistance. We also welcome contributions concerning the development of repurposed drug delivery systems to improve their bioavailability and/or targeting to augment therapeutic outcomes in various cancers. We will consider contributions demonstrating in vitro and/or in vivo preclinical evidence of drug repurposing and/or reformulation for cancer therapy, and encourage contributions focusing on the exploration of repurposed drugs as an adjunct to standard chemo- and/or radiotherapy.

We look forward to receiving your contributions.

Dr. Abhijit Date
Dr. Arati Sharma
Prof. Dr. Dhimant Desai
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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • drug repurposing
  • cancer
  • drug resistance
  • metastasis
  • drug delivery
  • liposomes
  • nanoparticles
  • bioavailability
  • drug targeting
  • reformulation

Published Papers (7 papers)

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Research

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10 pages, 1642 KiB  
Article
The Synthetic Collagen-Binding Peptide NIPEP-OSS Delays Mouse Myeloma Progression
by Syed Hassan Mehdi, Austin C. Gentry, Jue-Yeon Lee, Chong-Pyoung Chung and Donghoon Yoon
Cancers 2023, 15(9), 2473; https://doi.org/10.3390/cancers15092473 - 26 Apr 2023
Viewed by 1123
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy. It is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. An increasing amount of evidence shows [...] Read more.
Multiple myeloma (MM) is the second most common hematological malignancy. It is a clonal B-cell disorder characterized by the proliferation of malignant plasma cells in the bone marrow, the presence of monoclonal serum immunoglobulin, and osteolytic lesions. An increasing amount of evidence shows that the interactions of MM cells and the bone microenvironment play a significant role, suggesting that these interactions may be good targets for therapy. The osteopontin-derived collagen-binding motif-bearing peptide NIPEP-OSS stimulates biomineralization and enhances bone remodeling dynamics. Due to its unique targeted osteogenic activity with a broad safety margin, we evaluated the potential of NIPEP-OSS for anti-myeloma activity using MM bone disease (MMBD) animal models. In a 5TGM1-engrafted NSG model, the survival rates of the control and treated groups were significantly different (p = 0.0014), with median survival times of 45 and 57 days, respectively. The bioluminescence analyses showed that myeloma slowly developed in the treated mice compared to the control mice in both models. NIPEP-OSS enhanced bone formation by increasing biomineralization in the bone. We also tested NIPEP-OSS in a well-established 5TGM1-engrafted C57BL/KaLwRij model. Similar to the previous model, the median survival times of the control and treated groups were significantly different (p = 0.0057), with 46 and 63 days, respectively. In comparison with the control, an increase in p1NP was found in the treated mice. We concluded that NIPEP-OSS delays mouse myeloma progression via bone formation in MMBD mouse models. Full article
(This article belongs to the Special Issue Drug Repurposing and Reformulation for Cancer Treatment)
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17 pages, 2250 KiB  
Article
Chemotherapeutic Activity of Pitavastatin in Vincristine Resistant B-Cell Acute Lymphoblastic Leukemia
by Debbie Piktel, Javohn C. Moore, Sloan Nesbit, Samuel A. Sprowls, Michael D. Craig, Stephanie L. Rellick, Rajesh R. Nair, Ethan Meadows, John M. Hollander, Werner J. Geldenhuys, Karen H. Martin and Laura F. Gibson
Cancers 2023, 15(3), 707; https://doi.org/10.3390/cancers15030707 - 24 Jan 2023
Cited by 2 | Viewed by 1885
Abstract
B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor [...] Read more.
B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells. Based on the use of pitavastatin in acute myeloid leukemia (AML), we evaluated its efficacy in an REH ALL cell line derived to be resistant to vincristine. We found that pitavastatin inhibited the proliferation of both parental and vincristine-resistant REH tumor cells at an IC50 of 449 nM and 217 nM, respectively. Mitochondrial bioenergetic assays demonstrated that neither vincristine resistance nor pitavastatin treatment affected cellular oxidative phosphorylation, beta-oxidation, or glycolytic metabolism in ALL cells. In a co-culture model of ALL cells with bone marrow stromal cells, pitavastatin significantly decreased cell viability more robustly in the vincristine-resistant ALL cells compared with their parental controls. Subsequently, NSG mice were used to develop an in vivo model of B-cell ALL using both parental and vincristine-resistant ALL cells. Pitavastatin (10 mg/kg i.p.) significantly reduced the number of human CD45+ REH ALL cells in the bone marrow of mice after 4 weeks of treatment. Mechanistic studies showed that pitavastatin treatment in the vincristine-resistant cells led to apoptosis, with increased levels of cleaved PARP and protein-signaling changes for AMP-activated protein kinase/FoxO3a/Puma. Our data suggest the possible repurposing of pitavastatin as a chemotherapeutic agent in a model of vincristine-resistant B-cell ALL. Full article
(This article belongs to the Special Issue Drug Repurposing and Reformulation for Cancer Treatment)
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14 pages, 2568 KiB  
Article
Pitavastatin Is Anti-Leukemic in a Bone Marrow Microenvironment Model of B-Lineage Acute Lymphoblastic Leukemia
by Debbie Piktel, Rajesh R. Nair, Stephanie L. Rellick, Werner J. Geldenhuys, Karen H. Martin, Michael D. Craig and Laura F. Gibson
Cancers 2022, 14(11), 2681; https://doi.org/10.3390/cancers14112681 - 28 May 2022
Cited by 2 | Viewed by 1544
Abstract
The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown [...] Read more.
The lack of complete therapeutic success in the treatment of B-cell acute lymphoblastic leukemia (ALL) has been attributed, in part, to a subset of cells within the bone marrow microenvironment that are drug resistant. Recently, the cholesterol synthesis inhibitor, pitavastatin (PIT), was shown to be active in acute myeloid leukemia, prompting us to evaluate it in our in vitro co-culture model, which supports a chemo-resistant ALL population. We used phospho-protein profiling to evaluate the use of lipid metabolic active compounds in these chemo-resistant cells, due to the up-regulation of multiple active survival signals. In a co-culture with stromal cells, a shift towards anabolic processes occurred, which was further confirmed by assays showing increased lipid content. The treatment of REH leukemia cells with pitavastatin in the co-culture model resulted in significantly higher leukemic cell death than exposure to the standard-of-care chemotherapeutic agent, cytarabine (Ara-C). Our data demonstrates the use of pitavastatin as a possible alternative treatment strategy to improve patient outcomes in chemo-resistant, relapsed ALL. Full article
(This article belongs to the Special Issue Drug Repurposing and Reformulation for Cancer Treatment)
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Review

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19 pages, 2310 KiB  
Review
Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing
by RamaRao Malla, Sathiyapriya Viswanathan, Sree Makena, Shruti Kapoor, Deepak Verma, Alluri Ashok Raju, Manikantha Dunna and Nethaji Muniraj
Cancers 2024, 16(8), 1463; https://doi.org/10.3390/cancers16081463 - 11 Apr 2024
Viewed by 1122
Abstract
Cancer persists as a global challenge necessitating continual innovation in treatment strategies. Despite significant advancements in comprehending the disease, cancer remains a leading cause of mortality worldwide, exerting substantial economic burdens on healthcare systems and societies. The emergence of drug resistance further complicates [...] Read more.
Cancer persists as a global challenge necessitating continual innovation in treatment strategies. Despite significant advancements in comprehending the disease, cancer remains a leading cause of mortality worldwide, exerting substantial economic burdens on healthcare systems and societies. The emergence of drug resistance further complicates therapeutic efficacy, underscoring the urgent need for alternative approaches. Drug repurposing, characterized by the utilization of existing drugs for novel clinical applications, emerges as a promising avenue for addressing these challenges. Repurposed drugs, comprising FDA-approved (in other disease indications), generic, off-patent, and failed medications, offer distinct advantages including established safety profiles, cost-effectiveness, and expedited development timelines compared to novel drug discovery processes. Various methodologies, such as knowledge-based analyses, drug-centric strategies, and computational approaches, play pivotal roles in identifying potential candidates for repurposing. However, despite the promise of repurposed drugs, drug repositioning confronts formidable obstacles. Patenting issues, financial constraints associated with conducting extensive clinical trials, and the necessity for combination therapies to overcome the limitations of monotherapy pose significant challenges. This review provides an in-depth exploration of drug repurposing, covering a diverse array of approaches including experimental, re-engineering protein, nanotechnology, and computational methods. Each of these avenues presents distinct opportunities and obstacles in the pursuit of identifying novel clinical uses for established drugs. By examining the multifaceted landscape of drug repurposing, this review aims to offer comprehensive insights into its potential to transform cancer therapeutics. Full article
(This article belongs to the Special Issue Drug Repurposing and Reformulation for Cancer Treatment)
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24 pages, 2601 KiB  
Review
Don’t Judge a Book by Its Cover: The Role of Statins in Liver Cancer
by Natalia Piekuś-Słomka, Lavinia Patricia Mocan, Rezarta Shkreli, Cristiana Grapă, Kinga Denkiewicz, Oliwia Wesolowska, Miroslaw Kornek, Zeno Spârchez, Artur Słomka, Rareș Crăciun and Tudor Mocan
Cancers 2023, 15(20), 5100; https://doi.org/10.3390/cancers15205100 - 22 Oct 2023
Cited by 3 | Viewed by 1603
Abstract
Statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are an effective pharmacological tool for lowering blood cholesterol levels. This property makes statins one of the most popular drugs used primarily to prevent cardiovascular diseases, where hyperlipidemia is a significant risk factor that [...] Read more.
Statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are an effective pharmacological tool for lowering blood cholesterol levels. This property makes statins one of the most popular drugs used primarily to prevent cardiovascular diseases, where hyperlipidemia is a significant risk factor that increases mortality. Nevertheless, studies conducted mainly in the last decade have shown that statins might prevent and treat liver cancer, one of the leading causes of cancer-related mortality worldwide. This narrative review summarizes the scientific achievements to date regarding the role of statins in liver tumors. Molecular biology tools have revealed that cell growth and proliferation can be inhibited by statins, which further inhibit angiogenesis. Clinical studies, supported by meta-analysis, confirm that statins are highly effective in preventing and treating hepatocellular carcinoma and cholangiocarcinoma. However, this effect may depend on the statin’s type and dose, and more clinical trials are required to evaluate clinical effects. Moreover, their potential hepatotoxicity is a significant caveat for using statins in clinical practice. Nevertheless, this group of drugs, initially developed to prevent cardiovascular diseases, is now a key candidate in hepato-oncology patient management. The description of new drug-statin-like structures, e.g., with low toxicity to liver cells, may bring another clinically significant improvement to current cancer therapies. Full article
(This article belongs to the Special Issue Drug Repurposing and Reformulation for Cancer Treatment)
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28 pages, 6011 KiB  
Review
Repurposing of Chronically Used Drugs in Cancer Therapy: A Chance to Grasp
by Mohamad Ali Hijazi, André Gessner and Nahed El-Najjar
Cancers 2023, 15(12), 3199; https://doi.org/10.3390/cancers15123199 - 15 Jun 2023
Cited by 4 | Viewed by 2944
Abstract
Despite the advancement in drug discovery for cancer therapy, drug repurposing remains an exceptional opportunistic strategy. This approach offers many advantages (faster, safer, and cheaper drugs) typically needed to overcome increased challenges, i.e., side effects, resistance, and costs associated with cancer therapy. However, [...] Read more.
Despite the advancement in drug discovery for cancer therapy, drug repurposing remains an exceptional opportunistic strategy. This approach offers many advantages (faster, safer, and cheaper drugs) typically needed to overcome increased challenges, i.e., side effects, resistance, and costs associated with cancer therapy. However, not all drug classes suit a patient’s condition or long-time use. For that, repurposing chronically used medications is more appealing. This review highlights the importance of repurposing anti-diabetic and anti-hypertensive drugs in the global fight against human malignancies. Extensive searches of all available evidence (up to 30 March 2023) on the anti-cancer activities of anti-diabetic and anti-hypertensive agents are obtained from multiple resources (PubMed, Google Scholar, ClinicalTrials.gov, Drug Bank database, ReDo database, and the National Institutes of Health). Interestingly, more than 92 clinical trials are evaluating the anti-cancer activity of 14 anti-diabetic and anti-hypertensive drugs against more than 15 cancer types. Moreover, some of these agents have reached Phase IV evaluations, suggesting promising official release as anti-cancer medications. This comprehensive review provides current updates on different anti-diabetic and anti-hypertensive classes possessing anti-cancer activities with the available evidence about their mechanism(s) and stage of development and evaluation. Hence, it serves researchers and clinicians interested in anti-cancer drug discovery and cancer management. Full article
(This article belongs to the Special Issue Drug Repurposing and Reformulation for Cancer Treatment)
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24 pages, 2071 KiB  
Review
Perspectives of the Application of Non-Steroidal Anti-Inflammatory Drugs in Cancer Therapy: Attempts to Overcome Their Unfavorable Side Effects
by Vaikunthavasan Thiruchenthooran, Elena Sánchez-López and Anna Gliszczyńska
Cancers 2023, 15(2), 475; https://doi.org/10.3390/cancers15020475 - 12 Jan 2023
Cited by 7 | Viewed by 2567
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of [...] Read more.
Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature’s data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments. Full article
(This article belongs to the Special Issue Drug Repurposing and Reformulation for Cancer Treatment)
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