title: A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II.
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.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Cui
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Judy Yuet-Wa
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Faculty of Health Sciences, University of Macau, Macao, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Chuwen
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Luchen
authors.initials: L
authors.lastname: Shan
authors.affiliation: Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Changjiang
authors.initials: C
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Faculty of Health Sciences, University of Macau, Macao, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Di
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042963:Electron Transport Complex II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007773:Lactates / Q000494:pharmacology*; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C000625615:DT-010; D004791:Enzyme Inhibitors; D007773:Lactates; D011719:Pyrazines; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II
keywords: breast cancer; danshensu; mitochondrial complex II; reactive oxygen species; tetramethylpyrazine