Oncotarget

Research Papers:

A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

Liang Wang, Xiaojing Zhang, Guozhen Cui, Judy Yuet‑Wa Chan, Li Wang, Chuwen Li, Luchen Shan, Changjiang Xu, Qingwen Zhang, Yuqiang Wang, Lijun Di and Simon Ming‑Yuen Lee _

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Oncotarget. 2016; 7:32054-32064. https://doi.org/10.18632/oncotarget.8410

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Abstract

Liang Wang1,*, Xiaojing Zhang2,*, Guozhen Cui1, Judy Yuet-Wa Chan1, Li Wang3, Chuwen Li1, Luchen Shan2, Changjiang Xu2, Qingwen Zhang1, Yuqiang Wang2, Lijun Di3, Simon Ming-Yuen Lee1

1State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China

2Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China

3Faculty of Health Sciences, University of Macau, Macao, China

*These authors contributed equally to this work

Correspondence to:

Simon Ming-Yuen Lee, email: simonlee@umac.mo

Lijun Di, email: lijundi@umac.mo

Keywords: danshensu, tetramethylpyrazine, breast cancer, mitochondrial complex II, reactive oxygen species

Received: December 28, 2015     Accepted: March 02, 2016     Published: March 27, 2016

ABSTRACT

The mitochondrial respiratory chain, including mitochondrial complex II, has emerged as a potential target for cancer therapy. In the present study, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), DT-010, was synthesized. Our results showed that DT-010 is more potent than its parental compounds separately or in combination, in inhibiting the proliferation of MCF-7 and MDA-MB-231 cells by inducing cytotoxicity and promoting cell cycle arrest. It also inhibited the growth of 4T1 breast cancer cells in vivo. DT-010 suppressed the fundamental parameters of mitochondrial function in MCF-7 cells, including basal respiration, ATP turnover, maximal respiration. Treatment with DT-010 in MCF-7 and MDA-MB-231 cells resulted in the loss of mitochondrial membrane potential and decreased ATP production. DT-010 also promoted ROS generation, while treatment with ROS scavenger, NAC (N-acetyl-L-cysteine), reversed DT-010-induced cytotoxicity. Further study showed that DT-010 suppressed succinate-induced mitochondrial respiration and impaired mitochondrial complex II enzyme activity indicating that DT-010 may inhibit mitochondrial complex II. Overall, our results suggested that the antitumor activity of DT-010 is associated with inhibition of mitochondrial complex II, which triggers ROS generation and mitochondrial dysfunction in breast cancer cells.


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