title: Salinomycin, a p-glycoprotein inhibitor, sensitizes radiation-treated cancer cells by increasing DNA damage and inducing G2 arrest.
abstract: Salinomycin (Sal) is potentially useful for the treatment of cancer. The present study examined a novel mechanism of Sal sensitization in cancer cells. Sal sensitized radiation-treated cancer cells by inducing G2 arrest and causing DNA damage. Sal treatment also reduced p21 levels in radiation-treated cells. Considering that Sal sensitizes doxorubicin (DOX)- or etoposide (ETO)-treated cancer cells by causing DNA damage and reducing p21 expression, the results from our study suggest that the mechanism underlying Sal sensitization is conserved in both chemo- and radiation-treated cells. We also tested the ability of Sal to inhibit p-glycoprotein (P-gp), which plays a role in the efflux of anti-cancer drugs to reduce cellular damage. In particular, we compared Sal to verapamil (Ver), a well-known P-gp inhibitor. Sal inhibits P-gp with a different substrate distinct from that of Ver. In addition, Sal sensitized Ver-resistant cells, indicating that this compound is more effective for sensitizing than Ver. Taken together, the results from our study may contribute to the development of Sal-based therapy for cancer patients treated with P-gp-inhibiting drugs or radiation therapy.
authors.affiliation: Research Institute, National Cancer Center, 809 Madu 1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do 411-764, Republic of Korea.
authors.forename: Won Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Ju-Hwa
authors.initials: JH
authors.lastname: Kim
authors.forename: Kyungsil
authors.initials: K
authors.lastname: Yoon
authors.forename: Sunshin
authors.initials: S
authors.lastname: Kim
authors.forename: Jungsil
authors.initials: J
authors.lastname: Ro
authors.forename: Han Sung
authors.initials: HS
authors.lastname: Kang
authors.forename: Sungpil
authors.initials: S
authors.lastname: Yoon
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D011714:Pyrans / Q000494:pharmacology* / Q000627:therapeutic use*; D013379:Substrate Specificity / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use; D000095662:Polyether Polyketides
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011714:Pyrans; D014700:Verapamil; C010327:salinomycin; D000095662:Polyether Polyketides