Copper ions are novel therapeutic agents for uterine leiomyosarcoma

Abstract Background Multidrug resistance is a major concern in uterine leiomyosarcoma treatment. Development of effective chemotherapies and management of drug resistance in patients is necessary. The copper efflux transporter ATP7B is a member of the P-type ATPase family and is also known as a strong platinum efflux transporter. Various reports have shown the association between ATP7B and platinum resistance; however, suitable inhibitors or methods for inhibiting platinum efflux via ATP7B are not developed. Objective Our study focused on platinum resistance in uterine leiomyosarcoma. The role of ATP7B in uterine leiomyosarcoma resistance to platinum drugs was investigated both in vitro and in vivo. Methods ATP7B expression was investigated by western blotting and the efficacy of copper sulfate pretreatment and cisplatin administration in ATP7B-expressing cells was investigated both in vitro and in vivo . Results Western blot analysis of SK-LMS-1 (uterine leiomyosarcoma cell line) cells revealed strong ATP7B expression. A permanent SK-LMS-ATP7B-suppressed cell line (SK-LMS-7B cells) was generated and cisplatin exhibited a significant antitumor effect in SK-LMS-7B cells, both in vitro (SK-LMS-1 cells, IC 50 = 17.2 μM; SK-LMS-7B cells, IC 50 = 4.2 μM, p vs . 62.8%, p 50 decreased significantly compared with that in untreated cells and resulted in significantly increased intracellular platinum accumulation (1.9 pg/cell vs . 8.6 pg/cell, p in vivo and caused cisplatin to exhibit significantly increased antitumor effects in mice with SK-LMS-1 xenografts (3.1% vs . 62.7%, p Conclusions Our study demonstrates that ATP7B is overexpressed in uterine leiomyosarcoma cells and that copper sulfate, which acts as an inhibitor of platinum efflux via ATP7B, may be a therapeutic agent in the treatment of uterine leiomyosarcoma.