Existing drugs and their application in drug discovery targeting cancer stem cells

Abstract

Despite standard cancer therapies such as chemotherapy and targeted therapy have shown some efficacies, the cancer in many cases eventually relapses and metastasizes upon stopping the treatment. There is a small subpopulation of cancer cells within tumor, with specific characters similar to those found in stem cells. This group of cancer cells is known as tumor-initiating or cancer stem cells (CSCs), which have an ability to self-renew and give rise to cancer cell progeny. CSCs are related with drug resistance, metastasis and relapse of cancer, hence emerging as a crucial drug target for eliminating cancer. Rapid advancement of CSC biology has enabled researchers to isolate and culture CSCs in vitro, making the cells amenable to high-throughput drug screening. Recently, drug repositioning, which utilizes existing drugs to develop potential new indications, has been gaining popularity as an alternative approach for the drug discovery. As existing drugs have favorable bioavailability and safety profiles, drug repositioning is now actively exploited for prompt development of therapeutics for many serious diseases, such as cancer. In this review, we will introduce latest examples of attempted drug repositioning targeting CSCs and discuss potential use of the repositioned drugs for cancer therapy.

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth

“…These results suggest that cholesterol trafficking is a viable drug target and that inhibitors of endothelial cell cholesterol trafficking could be a new class of anti-angiogenic agents. This notion prompted us to screen the Johns Hopkins Drug Library (JHDL) [25, 26] to identify existing drugs that can modulate endothelial cell cholesterol trafficking. In this study, we successfully identified cholesterol trafficking inhibitors among existing drugs, including an anti-inflammatory drug cepharanthine (CEP).…”

Repurposing of Anthelminthics as Anticancer Drugs

“…Approval may be accelerated by knowledge of previous preclinical and clinical data on pharmacokinetics, side effects and regimens [5,87,88]. Anticancer activities of several anthelminthics attracted considerable interest, especially their capacity to target signal transduction pathways of CSCs/TICs of several tumor types.…”

Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations

“…Drug repurposing, also known as drug repositioning, drug re-tasking, drug reprofiling or therapeutic switching, is a way to obtain fast and cost-efficient drug discovery, since this strategy effectively enables the preclinical studies to be bypassed. Resources (DRUGSURV, Drug Repurposing Hub) are available for this "new tricks for old drugs" [7,[87][88][89]. Investigators can perform experimentation in silico, in vitro or in vivo in search for new targets of existing drugs.…”

“…Whether it is the compound's pleiotropic nature that leads to unexpected adverse effects is still unclear. For repurposed drugs, studies are needed to determine that they can reach the CSC niche [7].…”

“…Many CSC-targeting dietary phytochemicals can act synergistically with conventional anti-cancer agents. Recently, investigators discovered CSC-targeting repurposed drugs [7]. We advocate here a novel approach: combination therapy with the pairing of CSC-targeting phytochemicals and repositioned drugs.…”