Evodiamine synergizes with doxorubicin in the treatment of chemoresistant human breast cancer without inhibiting P-glycoprotein.

Shengpeng Wang,Lu Wang,Yitao Wang,Meiwan Chen,Zhangfeng Zhong,Zhi Shi,Ming Tan

doi:10.1371/journal.pone.0097512

Shengpeng Wang, Lu Wang + Show 5 more

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https://doi.org/10.1371/journal.pone.0097512

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Journal: PloS one	Publication Date: May 15, 2014
Citations: 100	License type: CC BY 4.0

Affiliation: University of Macau, Jinan University

Abstract

Drug resistance is one of the main hurdles for the successful treatment of breast cancer. The synchronous targeting of apoptosis resistance and survival signal transduction pathways may be a promising approach to overcome drug resistance. In this study, we determined that evodiamine (EVO), a major constituent of the Chinese herbal medicine Evodiae Fructus, could induce apoptosis of doxorubicin (DOX)-sensitive MCF-7 and DOX-resistant MCF-7/ADR cells in a caspase-dependent manner, as confirmed by significant increases of cleaved poly(ADP-ribose) polymerase (PARP), caspase-7/9, and caspase activities. Notably, the reversed phenomenon of apoptosis resistance by EVO might be attributed to its ability to inhibit the Ras/MEK/ERK pathway and the expression of inhibitors of apoptosis (IAPs). Furthermore, our results indicated that EVO enhanced the apoptotic action of DOX by inhibiting the Ras/MEK/ERK cascade and the expression of IAPs without inhibiting the expression and activity of P-glycoprotein (P-gp). Taken together, our data indicate that EVO, a natural product, may be useful applied alone or in combination with DOX for the treatment of resistant breast cancer.

Highlights

One of the most serious problems responsible for the failure of cancer chemotherapy in the clinic is the occurrence of multidrug resistance (MDR)
It has been suggested that increased drug efflux by one or more energy-dependent transporters, including P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs), and breast cancer resistance protein (BCRP), and changes in the targeted enzymes, altered cell cycle checkpoints and anti-apoptotic mechanisms could all result in MDR [3]
The cytotoxicity induced by EVO in MCF-7 and MCF-7/ADR cells was determined by lactate dehydrogenase (LDH) assay

Summary

Introduction

One of the most serious problems responsible for the failure of cancer chemotherapy in the clinic is the occurrence of multidrug resistance (MDR). Cancer cells can exhibit resistance to multiple functionally different agents, such as vinca alkaloids, anthracyclines and taxanes, after treatment with one type or class of drugs [1]. It has been suggested that increased drug efflux by one or more energy-dependent transporters, including P-glycoprotein (P-gp), multidrug resistance associated proteins (MRPs), and breast cancer resistance protein (BCRP), and changes in the targeted enzymes, altered cell cycle checkpoints and anti-apoptotic mechanisms could all result in MDR [3]. Apoptosis resistance and increased survival signaling are the major regulators of cancer cell survival against chemotherapy, and targeting only one of these pathways may be insufficient to obtain chemotherapeutic effects [4]. IAP antagonists have been shown to enhance the chemotherapeutic effect of different classes of cytotoxic drugs against various cancers [10]

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