Drug repurposing in cancer

Sleire, Linda; Førde, Hilde Elise; Netland, Inger Anne; Leiss, Lina; Skeie, Bente Sandvei; Enger, Per Øyvind

doi:10.1016/j.phrs.2017.07.013

Cited by 286 publications

(228 citation statements)

References 290 publications

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“…As gene-centered treatment and drug repurposing attracts increasing interest (1,3,59), we expect the GUST method and the online database will facilitate discoveries of clinically actionable targets.…”

Section: Discussionmentioning

confidence: 99%

Contextual Classifications of Cancer Driver Genes

Chandrashekar

Ahmadinejad

Wang

et al. 2019

Preprint

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Functions of cancer driver genes depend on cellular contexts that vary substantially across tissues and organs. Distinguishing oncogenes (OGs) and tumor suppressor genes (TSGs) for each cancer type is critical to identifying clinically actionable targets. However, current resources for context-aware classifications of cancer drivers are limited. In this study, we show that the direction and magnitude of somatic selection of missense and truncating mutations of a gene are suggestive of its contextual activities. By integrating these features with ratiometric and conservation measures, we developed a computational method to categorize OGs and TSGs using exome sequencing data. This new method, named genes under selection in tumors (GUST) shows an overall accuracy of 0.94 when tested on manually curated benchmarks. Application of GUST to 10,172 tumor exomes of 33 cancer types identified 98 OGs and 179 TSGs, >70% of which promote tumorigenesis in only one cancer type. In broad-spectrum drivers shared across multiple cancer types, we found heterogeneous mutational hotspots modifying distinct functional domains, implicating the synchrony of convergent and divergent disease mechanisms. We further discovered two novel OGs and 28 novel TSGs with high confidence.The GUST program is available at https://github.com/liliulab/gust. A database with pre-computed classifications is available at https://liliulab.shinyapps.io/gust

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Section: Discussionmentioning

confidence: 99%

Contextual Classifications of Cancer Driver Genes

Chandrashekar

Ahmadinejad

Wang

et al. 2019

Preprint

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“…In contrast to de novo development of new medicines, drug repurposing represents an alternative way of improving success rate, shortening processing time and cutting costs of cancer drug development (Sleire et al, 2017;Hernandez et al, 2017). Drug repurposing, also known as drug repositioning, reprofiling, redirecting or retasking, is a drug development strategy of finding new indications for already licensed or failed drugs apart from its original indication (Pantziarka et al, 2014;Yadav & Talwar, 2019;Sleire et al, 2017;Hernandez et al, 2017;Fong & To, 2019).…”

Section: Introductionmentioning

confidence: 99%

Nitroxoline: repurposing its antimicrobial to antitumor application

Mitrović

Kos

2019

Acta Biochim Pol

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Cancer is a disease receiving an outstanding input of funds for basic and clinical research but is, nevertheless, still the second leading cause of death in the developed world and a great burden for health systems. New drugs are therefore needed to improve therapy, prolong survival of cancer patients and improve their quality of life. The high cost of development and clinical evaluation of new drugs limits the number that actually enter clinical use. To overcome this problem, repurposing of established drugs for new indications has gained a lot of interest, especially in the field of oncology. The well-established antimicrobial agent nitroxoline has been identified as a promising candidate to be repurposed for cancer treatment in several independent studies. Here we have reviewed a wide range of molecular mechanisms and tumor models involving nitroxoline in impairment of tumor progression. Furthermore, nitroxoline was used as a lead compound for structure-based chemical synthesis of new derivatives in order to improve its potency as well as selectivity for various targets. The potent antitumor activity of nitroxoline points strongly in the direction of its repurposing for cancer treatment and to the benefits of this strategy for patients and healthcare system.

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“…For example, diabetes is associated with an increased MM incidence, and metformin has been found to possess the ability to inhibit the development of MM both in vitro and in vivo [7,8]. Amounting evidence indicates that metformin also possesses anti-tumor effects against different cancers such as melanoma, colon cancer, ovarian cancer, lung cancer, bladder cancer and prostate cancer [9][10][11]. Moreover, several preclinical and clinical studies have shown the beneficial effects of metformin in cancer treatment, and few serious adverse events were observed [12,13].…”

Section: Introductionmentioning

confidence: 99%

Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells

Zhao

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new therapeutic options that bypass these resistance mechanisms. Metformin is a widely prescribed antidiabetic drug with direct antitumor activity against various tumor cell lines. FTY720, also known as fingolimod, is an immune-modulating agent approved by the FDA as oral medication to treat the relapsing form of multiple sclerosis (MS). In recent years, FTY720 has attracted attention due to its anti-tumor activity. To explore an optimized combinational therapy, interactions between metformin and FTY720 were examined in MM cells. Methods: MTT assays were employed to assess the viability of MM cells. An apoptotic nucleosome assay was employed to measure apoptosis. Loss of mitochondrial membrane potential (MMP, ΔΨm) and cellular levels of ROS were measured by flow cytometry. qRT-PCR was used to analyze the expression of mRNAs. Western blotting assays were applied to measure the levels of proteins involved in different signaling pathways. Results: Coadministration of metformin and FTY720 synergistically inhibited the proliferation of MM cells. Increased levels of apoptosis, activation of caspase-3 and cleavage of PARP were detected after cotreatment with metformin and FTY720. These events were associated with modulation of Bcl-2 proteins, loss of MMP, ER stress induction, and inhibition of the PI3K/AKT/mTOR signaling pathway. The metformin/FTY720 regimen markedly induced ROS generation; moreover, apoptosis, ER stress and inhibition of PI3K/AKT/ mTOR were attenuated by the ROS scavenger NAC. Conclusions: Exposure to metformin in combination with FTY720 potently induces apoptosis in MM cells in a ROS-dependent manner, suggesting that a strategy combining these agents warrants further investigation in MM.

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Drug repurposing in cancer

Cited by 286 publications

References 290 publications

Contextual Classifications of Cancer Driver Genes

Contextual Classifications of Cancer Driver Genes

Nitroxoline: repurposing its antimicrobial to antitumor application

Metformin and FTY720 Synergistically Induce Apoptosis in Multiple Myeloma Cells

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