Anticancer efficacy of a nitric oxide-modified derivative of bifendate against multidrug-resistant cancer cells.

Zhiguang Ren,Hui Peng,Xiaoke Gu,Jiannan Feng,Jizhen Lin,Yaqiong Chen,Guojiang Chen,Yihua Zhang,Bin Lu

doi:10.1111/jcmm.12796

Abstract

The development of multidrug resistance (MDR) not only actively transports a wide range of cytotoxic drugs across drug transporters but is also a complex interaction between a number of important cellular signalling pathways. Nitric oxide donors appear to be a new class of anticancer therapeutics for satisfying all the above conditions. Previously, we reported furoxan‐based nitric oxide‐releasing compounds that exhibited selective antitumour activity in vitro and in vivo. Herein, we demonstrate that bifendate (DDB)‐nitric oxide, a synthetic furoxan‐based nitric oxide‐releasing derivative of bifendate, effectively inhibits the both sensitive and MDR tumour cell viability at a comparatively low concentration. Interestingly, the potency of DDB‐nitric oxide is the independent of inhibition of the functions and expressions of three major ABC transporters. The mechanism of DDB‐nitric oxide appears to be in two modes of actions by inducing mitochondrial tyrosine nitration and apoptosis, as well as by down‐regulating HIF‐1α expression and protein kinase B (AKT), extracellular signal‐regulated kinases (ERK), nuclear factor κB (NF‐κB) activation in MDR cells. Moreover, the addition of a typical nitric oxide scavenger significantly attenuated all the effects of DDB‐nitric oxide, indicating that the cytotoxicity of DDB‐nitric oxide is as a result of higher levels of nitric oxide release in MDR cancer cells. Given that acquired MDR to nitric oxide donors is reportedly difficult to achieve and genetically unstable, compound like DDB‐nitric oxide may be a new type of therapeutic agent for the treatment of MDR tumours.

Highlights

Multidrug resistance (MDR) in cancer has become a serious obstacle to successful clinical cancer chemotherapy
It has been reported previously that potential resistant mechanism of actions include the activation of the Ras/Raf/MEK/extracellular signal-regulated kinases (ERK) and PI3K/ AKT pathway as well as key transcription factors such as nuclear factor jB (NF-jB) and HIF-1a that play a central role in proliferation and survival of cancer cells [7]
To investigate if the effects of DDB-nitric oxide on MDR cells via the inhibition of these key signalling pathways, we examined the levels of total HIF-1a and phosphorylated forms of AKT, ERK, NF-jB after treatment with DDB-nitric oxide in the resistant cells

Summary

Introduction

Multidrug resistance (MDR) in cancer has become a serious obstacle to successful clinical cancer chemotherapy. The preliminary mechanism studies suggest that the potent inhibitory effects of DDB-nitric oxide is independent of the inhibition of three major drug transporters, but mostly relies on the promotion of mitochondrial tyrosine nitration and apoptosis, as well as the down-regulation of HIF-1a expression and AKT, ERK, and NF-jB activation via high levels of nitric oxide release in MDR cells.

Results

Conclusion