Eswar Shankar
Vish Subramaniam
Dharmaraja Allimuthu- 1Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
- 2Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH, United States
- 3Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar Pradesh, India
Editorial on the Research Topic
Adopting drug repurposing to overturn drug resistance in cancer
Introduction
Despite significant technological advances the etiology of cancer and mechanism disease progression, and their translation into therapeutic benefits has been considerably slow. Traditional drug discovery efforts employing unbiased or target-based approaches involving natural products or small-molecule screening have created several therapeutics, but the entire process is tedious. Drug repurposing, also called drug repositioning, reprofiling, or retasking, identifies opportunities to use approved or investigational drugs that are outside the scope of the original medical indications (Ashburn and Thor, 2004). This strategy can be advantageous over developing an entirely new drug or formulation for a condition. It lowers the risk of failure as the repurposed drug’s safety has already been determined and found to be safe in preclinical models and humans through completed early-stage trials; thus, from a safety point of view, the drug is less likely to fail in subsequent efficacy trials (Breckenridge and Jacob, 2019). Drug resistance is a recurrent issue in oncology (Maxmen, 2016; Dharmaraja, 2017; Nikolaou et al., 2018) and researchers are actively pursuing innovative strategies to mitigate its impact. These approaches encompass a range of interventions, including immuno-oncological treatments that elicit the immune system’s response to target cancer cells (Dawe et al., 2020), combination therapies employing multiple drugs to attack cancer cells at different levels (Obenauf, 2022), and precision medicine that focuses on the molecular pathways underlying drug resistance to optimize treatment outcomes (Tsimberidou et al., 2020). These novel techniques aim to surmount the challenges of drug resistance in cancers and enhance patient outcomes. Repurposing drugs for cancer treatment has emerged as an increasingly attractive strategy as it can reduce the time to regulatory approval (Bertolini et al., 2015; Clohessy and Pandolfi, 2015; Corsello et al., 2017; Pantziarka, 2017; Pushpakom et al., 2019). In this Research Topic, we have collated research reports exploring the utility of organic small molecules, natural products, Chinese herbal medicines, and antibodies as combinatorial therapies to target drug resistance in cancers (Figure 1).
FIGURE 1. Summary of repurposed small molecules and their mechanism of actions to tackle drug resistance in the panel of cancers mentioned.
Small molecules in combination therapy for cancer treatment
Small molecules with promising anticancer effects have a high possibility of becoming commercialized. Therefore, there is growing enthusiasm for exploring small molecules to advance the potency of existing anticancer therapeutics. A report by Chandrasekaran et al. has identified a tyrosinated-urolithin A derivative, ARS-600, as an effective inhibitor (EC50: <920 nM) of castration-resistant prostate cancer (CRPC) in xenografted castrated and non-castrated mice. The mechanism of the lead molecules was found to be the ubiquitination of the androgen receptor and its splice variant ARV7 resulting in signal inhibition in CRPC cells. Similarly, Saran et al. have identified a Withaferin A analog, ASR490, as an inhibitor of NOTCH-NICD (an active form of Notch1) in breast cancer stem cells at nanomolar concentrations. ASR490 triggers autophagy in cells to prevent cancer progression in in vivo xenograft models. High-throughput screening of bioactive molecules could help with the rapid identification of potential therapeutics and could provide insights into the mechanism of action. Huang et al. performed a quantitative high-throughput combinational screening of the LOPAC library (1,280 molecules, Sigma) and identified terfenadine (TFD) as a potential sensitizer of multidrug-resistant (MDR) ovarian cancer cells to doxorubicin. Here TFD molecule exerts a synergistic effect with doxorubicin against the survival of MDR ovarian cancer. They established that the mechanism of TFD function is not the manipulation of its canonical targets (Histamine receptor 1 or ether-a-go-go-related gene (hERG) channel), but direct modulation of the calcium-mediated signaling (CAMKIID/CREB1) pathway. Another small molecule-based combination therapeutic strategy with a flavonoid natural product, wogonin, was studied by Zhang et al. They show that gemcitabine-resistant pancreatic cancer cells became sensitive to gemcitabine when co-treated with wogonin. Subsequent mechanism-of-action analysis revealed suppression of the protein kinase B (Akt) signaling pathway with wogonin treatment resulting in apoptosis induction in vivo. Niu et al. have demonstrated that an antidepressant and antineoplastic drug, venlafaxine, could be used to control melanoma in mouse models. Venlafaxine induced apoptosis in melanoma through its interaction with JNK1/2 signaling to promote translocation of Nur77 to mitochondria, which triggered the activation of Bcl-2, cleaved caspase-3, and poly-ADP ribose polymerase (PARP) in mouse models.
Natural products and herbal medicines that help overcome drug resistance
Natural products are a rich source of structurally diverse chemical scaffolds for the screening and identification of unique therapeutic candidates. This should not be a surprise given the successful development of taxanes as chemotherapeutic agents since the 1960s (Weaver, 2014). Chen et al. explored the therapeutic potential of kaempferol (KPL), a flavonoid natural product isolated from persimmon leaves. Here, they evaluate the efficacy of KPL on resensitizing drug-resistant hepatocellular carcinoma (HepG2) cells to venetoclax (ABT-199), a therapeutic approved to treat leukemia. The combination of KPL with ABT-199 demonstrated the induction of apoptosis through the disruption of mitochondrial membrane potential and the release of cytochrome C into mitochondria and cytoplasm, triggering apoptosis. The downstream apoptotic signature was observed in the reduction in anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Mcl-1 and the upregulation of cleaved caspase. Traditional Chinese medicines have been used for the treatment of cancer for several decades. For example, Sang et al. showed that feiyanning formula (FYN), a Chinese herbal medicine cocktail prescribed for the treatment of lung cancer, could be exploited for targeting osimertinib-resistant non-small cell lung cancer (NSCLC). FYN has been shown to downregulate SRSF1 and GSK3β and thereby modulate the Wnt/β-catenin pathway in osimertinib-resistant NSCLC, HCC827OR, and PC9OR cells. Further, FYN (250 μg/mL) was found to elicit a synergistic effect with osimertinib (4 µM), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, on osimertinib-resistant NSCLC cells after 48 h of treatment and to prevent cell proliferation and migration; the combination suppressed tumor growth in mouse xenograft models of lung adenocarcinoma. Another Chinese herbal formula, feiyiliu mixture (FYLM), was described as sensitizing mutant EGFR-NSCLC to osimertinib by Shi et al. The major components of FYLM, characterized by mass spectrometry, included several antioxidant components such as quercetin, apigenin, formononetin, scutellarin, and oleanolic acid. EGFR-Del19/T790M/C797S mutant NSCLC is resistant to osimertinib; when combined with FYLM, the cells underwent apoptosis. It was shown that FYLM reduced EGFR phosphorylation and downregulated cyclin B1 and Bcl-2 while upregulating levels of cleaved caspase-3 to promote apoptosis in vivo. Peng et al. performed a metadata analysis of 31,263 patients treated with 16 Chinese herbal injections (CHIs) in combination with Western medicines. In a detailed analysis of 16 CHIs used either alone or in combination to treat cancer in China, a few were shown to be exceptionally beneficial in terms of reducing gastrointestinal adverse reactions, the incidence of thrombocytopenia, and the incidence of leukopenia when combined with Western medicines.
Antibody and nanocarrier systems targeting drug resistance
Antibodies and antibody-drug conjugates (ADCs) that have been approved by the FDA for use in cancer treatment are promising classes of cancer therapies and precision medicines. However, the inherent reduction in activity due to de novo resistance development in the phenotype has prompted the combination therapies evolution of ADCs with chemotherapeutics. Lv et al. describe a case report of overcoming trastuzumab resistance in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer by treating it with a triple regimen of apatinib and camrelizumab with trastuzumab. This issue also includes a research article on nanoparticle-based drug delivery systems for cancer treatment. Here, Wu et al. have developed a trifunctional, covalent nanocarrier system (Pep-1@PDA-TMZ) as a chemotherapeutic and photothermal therapeutic (PTT) to treat glioblastoma. This Pep-1@PDA-TMZ is based on dopamine polymeric nanoparticles covalently linked to a glioblastoma drug, temozolomide (TMZ), and Pep-1, a cell-penetrating peptide for enabling blood-brain barrier (BBB) breach. The conjugate Pep-1@PDA-TMZ was shown to penetrate cells effectively and was delivered specifically to the therapeutic site with a 77% inhibition of U87 cells in tumor-bearing nude mice in vivo recorded upon irradiation. This Research Topic also includes reviews by Xia et al. and Wang et al. that comprehensively discuss combination therapeutic strategies to overcome PARP-mediated drug resistance in breast and gynecological cancers.
This Research Topic assembles research reports targeting a wide range of cancers and mechanisms centered around overcoming drug resistance by utilizing drug repurposing or therapies using combinations of drugs (Figure 1).
Author contributions
ES led the team of DA and VS as Guest Editors of this Research Topic and the team closely interacted throughout the editorial process, by defining the subjects to be treated and by acting as handling editors of the manuscripts submitted to the Research Topic and writing the Editorial. All authors contributed to the article and approved the submitted version.
Acknowledgments
We thank Angela Dahlberg, Senior Editor, Division of Medical Oncology, The Ohio State University Wexner Medical Center, for the final language editing to improve the clarity of presentation.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: cancer drug resistance, drug repurposing, FDA-approved drugs, natural product, combination therapy
Citation: Shankar E, Subramaniam V and Allimuthu D (2023) Editorial: Adopting drug repurposing to overcome drug resistance in cancer. Front. Cell Dev. Biol. 11:1191682. doi: 10.3389/fcell.2023.1191682
Received: 22 March 2023; Accepted: 03 April 2023;
Published: 28 April 2023.
Edited and reviewed by:
Shyamala Maheswaran, Massachusetts General Hospital and Harvard Medical School, United StatesCopyright © 2023 Shankar, Subramaniam and Allimuthu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dharmaraja Allimuthu, atdharma@iitk.ac.in; Eswar Shankar, shankar.109@osu.edu; Vish Subramaniam, subramaniam.1@osu.edu