Identification of chemosensitizers by drug repurposing to enhance the efficacy of cancer therapy

Introduction

The development of drug resistance, which eventually leads to therapy failure and tumor relapse, emerges as a major challenge in cancer treatment. Clinic drug resistance is featured by the resistance toward a broad spectrum of drugs, which are structurally and functionally unrelated, i.e., multidrug resistance (MDR). Both intrinsic and acquired drug resistance are attributed to at least one of the following mechanisms: (a) altered expression of drug efflux transporters; (b) sequestration of drugs mediated by acidic cellular vesicles [ ]; (c) enhanced drug biotransformation and metabolism [ , ]; (d) impairment of apoptosis through DNA repair augment [ ], checkpoint activation [ ] or cellular stress harness [ , ]; (e) stemness induction and epithelial–mesenchymal transition (EMT) [ ]; (f) altered epigenomics by methylation, acetylation, and microRNA (miRNA) regulation [ ]; and (g) mutations of drug targets [ ] ( Fig. 11.1 ).

In order to combat MDR, chemosensitizers aiming to improve the efficacy of standard cytotoxic regimens have been proposed and developed accordingly. In principle, drugs reversing the resistance mechanisms, except for targets mutations, are able to restore cellular sensitivity toward chemotherapies ( Fig. 11.1 ): (1) drugs restraining efflux transporters can enhance intracellular dose of chemotherapies; (2) drugs disrupting acidic cellular vesicles can prevent vesicle sequestration of cytotoxic agents and thereby enhance the accessibility of chemotherapies to their targets; (3) inhibitors of metabolic enzymes responsible for biotransformation can elevate the concentration of therapeutically effective drugs; (4) drugs exhibiting concomitant effects on cellular process including oncogenic signaling, cell cycle, DNA repair, stress handling, or energy supply can augment the apoptosis induced by anticancer agents; (5) drugs reversing EMT process can sensitize tumors toward treatment; and (6) miRNAs negatively regulating prosurvival gene expression can promote apoptosis induced by anticancer agents. The first three types of chemosensitizers aiming at enhancing the therapeutic concentration of anticancer agents are referred to as quantitative chemosensitizers in this chapter, while the latter three types aiming at improving the killing effect of anticancer agents are referred to as qualitative chemosensitizers.

Noticeably, numerous drugs already existing on the market as clinically approved medications for a broad range of indications outside oncology exhibit potent potential to restore cellular response through abovementioned mechanisms. Considering the high failure rates and costs during conventional drug development, repurposing of these drugs to enhance tumor response toward chemotherapies is considered to be a more efficient and economical strategy. In this chapter, clinically approved drugs with chemosensitizing properties and their functional mechanisms will be discussed in depth.

Quantitative chemosensitizers

ATP-binding cassette transporters inhibitors

Insufficient drug accumulation in tumor cells due to overexpression of energy-dependent efflux transporters accounts for a large proportion of MDR cases. These drug transporters belong to the ATP-binding cassette (ABC) transporter family and are characterized by the capacity of binding and extruding drugs against the concentration gradient at the expense of ATP hydrolysis. A total of 49 members of the family were found in the human genome, which are divided into seven subfamilies designated from A to G [ ]. In this chapter, we concentered on the most prominent ABC transporters, i.e., P-glycoprotein (P-gp, also known as MDR1 or ABCB1), MDR-associated protein family members (MRP, also known as ABCC), and breast cancer–resistance protein (BCRP, also known as ABCG2, MXR, or ABC-P) ( Fig. 11.2 ). They confer resistance toward a broad range of anticancer agents ( Table 11.1 ) through conformational change. Taking P-gp as an example, P-gp adopts an inward-face conformation showing a turned V-like structure, which forms the main substrate binding cavity at the inner leaflet of the membrane [ ]. Upon binding to its substrates at the top of the turned “V” structure, each of the two NBDs recruit one ATP molecule. Accompanied by ATP hydrolysis, P-gp undergoes conformational change, which eventually opens the inner membrane and allows access of the bound substrates to the periplasm. Similar to P-gp, the substrate transportation of MRP depends on conformation alteration upon hydrolysis of ATP molecules [ ]. However, the concrete process in BCRP has not been demonstrated. Due to the structural specificity of BCRP, many studies have indicated that BCRP requires homodimerization [ ] or higher-order oligomerization [ ].

Table 11.1

Resistance to anticancer agents mediated by three principal ABC transporters involved in MDR.

Drug classification		Resistance-mediating proteins
		P-gp	MRP1	BCRP
Topoisomerase I inhibitors	Irinotecan/SN-38	R	R	R
	Topotecan	R	R	R
	Methotrexate/MTX		R	R
Topoisomerase II inhibitors/anthracyclines	Doxorubicin	R	R	R
	Daunorubicin	R		R
	Epirubicin	R	R	R
	Mitoxantrone	R	R	R
	Bisantrene	R		R
Topoisomerase II inhibitors/epipodophyllotoxins	Etoposide/VP-16	R	R
	Teniposide/VM-26	R	R
Vinca alkaloids	Vinblastine	R	R
	Vincristine	R	R
	Vinorelbine	R
	Catharanthine	R
Taxanes	Docetaxel	R
	Paclitaxel	R
Antibiotics	Actinomycin D	R
	Mitomycin	R
Tyrosine kinase inhibitors	Imatinib	R	R	R
	Gefitinib		R	R
CDK inhibitor	Flavopiridol/alvocidib			R
Others	Rhodamine 123	R		R

R indicates resistance conferred by the protein toward a certain clinic drug. The drugs are compiled from elegant studies [ ].