New perspectives of cobalt tris(bipyridine) system: anti-cancer effect and its collateral sensitivity towards multidrug-resistant (MDR) cancers

// Betty Yuen Kwan Law 1, * , Yuan Qing Qu 1, * , Simon Wing Fai Mok 1 , Hauwei Liu 2 , Wu Zeng 1 , Yu Han 1 , Flora Gordillo-Martinez 1 , Wai-Kit Chan 1 , Keith Man-Chung Wong 2 and Vincent Kam Wai Wong 1 1 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, P.R. China 2 Department of Chemistry, South University of Science and Technology of China, Tangchang Boulevard, Nanshan District, Shenzhen, P.R. China * These authors contributed equally to this work Correspondence to: Vincent Kam Wai Wong, email: bowaiwong@gmail.com Keith Man-Chung Wong, email: keithwongmc@sustc.edu.cn Keywords: cobalt complexes, collateral sensitivity, autophagy, anti-cancer, drug-resistant cancer Received: January 10, 2017      Accepted: June 16, 2017      Published: July 05, 2017 ABSTRACT Platinating compounds including cisplatin, carboplatin, and oxaliplatin are common chemotherapeutic agents, however, patients developed resistance to these clinical agents after initial therapeutic treatments. Therefore, different approaches have been applied to identify novel therapeutic agents, molecular mechanisms, and targets for overcoming drug resistance. In this study, we have identified a panel of cobalt complexes that were able to specifically induce collateral sensitivity in taxol-resistant and p53-deficient cancer cells. Consistently, our reported anti-cancer functions of cobalt complexes 1–6 towards multidrug-resistant cancers have suggested the protective and non-toxic properties of cobalt metal-ions based compounds in anti-cancer therapies. As demonstrated in xenograft mouse model, our results also confirmed the identified cobalt complex 2 was able to suppress tumor growth in vivo . The anti-cancer effect of the cobalt complex 2 was further demonstrated to be exerted via the induction of autophagy, cell cycle arrest, and inhibition of cell invasion and P-glycoprotein (P-gp) activity. These data have provided alternative metal ion compounds for targeting drug resistance cancers in chemotherapies.