Tetrandrine induces autophagy and differentiation by activating ROS and Notch1 signaling in leukemia cells.

Ting Liu,Guixian Wu,Wenhua Li,Chunrong Yu,Qiuxu Men,Zan Huang,Xin Liu

doi:10.18632/oncotarget.3505

Abstract

All-trans retinoic acid (ATRA) is a differentiating agent for the treatment of acute promyelocytic leukemia (APL). However, the therapeutic efficacy of ATRA has limitations. Tetrandrine is a traditional Chinese medicinal herb extract with antitumor effects. In this study, we investigated the effects of tetrandrine on human PML-RARα-positive acute promyelocytic leukemia cells. Tetrandrine inhibited tumors in vivo. It induced autophagy and differentiation by triggering ROS generation and activating Notch1 signaling. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. The in vivo results indicated that low concentrations of tetrandrine inhibited leukemia cells proliferation and induced autophagy and then facilitated their differentiation, by activating ROS and Notch1 signaling. We suggest that tetrandrine is a potential agent for the treatment of APL by inducing differentiation of leukemia cells.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hemopoietic progenitor cells
All-trans-retinoic acid (ATRA) is currently the most efficient agent used in differentiation therapy of acute myeloid leukemia (AML)
Higher clinical efficiency in acute promyelocytic leukemia (APL) patients is achieved by a combination of All-trans retinoic acid (ATRA) with arsenic trioxide (ATO) [12, 36, 37], the development of chemotherapeutic differentiation therapies is still limited

Summary

INTRODUCTION

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hemopoietic progenitor cells. We previously reported that high concentrations of tetrandrine effectively induce apoptosis, and low doses of tetrandrine induce cellular autophagy in liver cancer cells and show good synergistic antitumor effects in combination with other chemotherapeutic agents [32,33,34]. We found that tetrandrine is a potent agonist for cell autophagy in many types of cancer cells and even exhibits a much stronger activity than rapamycin for inducing autophagy [35]. Tetrandrine induced autophagy and differentiation in M5 type patient primary leukemia cells. These findings provide a novel chemotherapeutic strategy for APL, even in AML patients, with the development of tetrandrine as a differentiationinducing agent

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS