Semi-synthetic ocotillol analogues as selective ABCB1-mediated drug resistance reversal agents.

Yun-Kai Zhang,Guan-Nan Zhang,Jinyi Xu,Bhargav A Patel,Hengyuan Zhang,Yi-Jun Wang,Rui Si,Rishil J Kathawala,Zhe-Sheng Chen

doi:10.18632/oncotarget.4493

Abstract

Overexpression of ATP-Binding Cassette transporters leads to multidrug resistance in cancer cells and results in the failure of chemotherapy. In this in-vitro study, we investigated whether or not (20S, 24R/S)-epoxy-12β, 25-dihydroxy-dommarane-3β-amine (ORA and OSA), a pair of semi-synthetic ocotillol analogue epimers, could inhibit the ABCB1 transporter. ORA (1 μM and 3 μM) significantly reversed the resistance to paclitaxel and vincristine in ABCB1-overexpressing SW620/Ad300 and HEK/ABCB1 cells, whereas OSA had no significant effects. In addition, ORA (3 μM) significantly increased the intracellular accumulation of [3H]-paclitaxel by suppressing the efflux function of ABCB1. Meanwhile, both ORA (3 μM) and OSA (3 μM) did not significantly alter the expression level or the subcellular location of ABCB1 protein. Moreover, the ABCB1 ATPase study suggested that ORA had a stronger stimulatory effect on the ATPase activity than OSA. ORA also exhibited a higher docking score as compared with OSA inside transmembrane domain of ABCB1. Overall, we concluded that ORA reverse ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function.

Highlights

Multi-drug resistance (MDR) is the condition that enables cancerous cells to resist antineoplastic compounds with a wide variety of chemical structures and mechanisms, and is a major cause of chemotherapy failure [1]
In order to investigate the effects of ORA and OSA on ATP-binding cassette (ABC) transporters, we first examined the sensitivity of ABCB1, ABCG2, and ABCC1-overexpressing cells to ORA and OSA
We further examined whether ORA and OSA could increase the sensitivity of ABCB1-expressing drugresistant cells to substrate drugs

Summary

Introduction

Multi-drug resistance (MDR) is the condition that enables cancerous cells to resist antineoplastic compounds with a wide variety of chemical structures and mechanisms, and is a major cause of chemotherapy failure [1]. ATP-binding cassette (ABC) transporters utilize the energy generated by ATP hydrolysis to transport various substrates across cellular membranes, contributing to elevated drugefflux effect in cancer cells [4, 5]. The third-generation includes inhibitors such as LY335979, VX-710, and XR-9576 [14] These compounds either have severe side effects or alter the pharmacokinetic profile of anticancer drugs, so their application is impeded [15, 16]. Discovery of a novel lead compound as ABCB1 inhibitor is still urgent and promising for overcoming MDR in cancer chemotherapy

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