title: A novel anthracene derivative, MHY412, induces apoptosis in doxorubicin-resistant MCF-7/Adr human breast cancer cells through cell cycle arrest and downregulation of P-glycoprotein expression.
abstract: New potential chemotherapeutic strategies are required to overcome multidrug resistance (MDR) in cancer. This study investigated the anticancer effect of a novel anthracene derivative MHY412 on doxorubicin-resistant human breast cancer (MCF-7/Adr) cells. We measured cell viability and the expression of apoptosis-related genes; in addition, the antitumor activity of MHY412 was confirmed using an in vivo tumor xenograft model. MHY412 significantly inhibited the proliferation of MCF-7/Adr and MCF-7 cells in a concentration-dependent manner. Notably, the half-maximal inhibitory concentration (IC50) values of MHY412 in MCF-7/Adr (0.15 µM) and MCF-7 (0.26 µM) cells were lower than those of doxorubicin (MCF-7/Adr, 13.6 µM and MCF-7, 1.26 µM) after treatment for 48 h. MHY412 at low concentrations induced S phase arrest, but at high concentrations, the number of MCF-7/Adr cells in the sub-G1 phase significantly increased. MHY412-induced sub-G1 phase arrest was associated with inhibition of cyclin, cyclin-dependent kinase 2 (CDK2) and p21 expression in MCF-7/Adr cells. MHY412 markedly reduced P-glycoprotein (P-gp) expression and increased apoptotic cell death in MCF-7/Adr cells. Cleavage of poly-ADP ribose polymerase, reduced Bcl-2 expression, and increased in cytochrome c release in MCF-7/Adr cells confirmed the above results. In addition, MHY412 markedly inhibited tumor growth in a tumor xenograft model of MCF-7/Adr cells. Our data suggest that MHY412 exerts antitumor effects by selectively modulating the genes related to cell cycle arrest and apoptosis. In particular, MHY412 is a new candidate agent for the treatment of Bcl-2 overexpressed doxorubicin-resistant human breast cancer.
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Umasankar
authors.initials: U
authors.lastname: De
authors.forename: Pusoon
authors.initials: P
authors.lastname: Chun
authors.forename: Wahn Soo
authors.initials: WS
authors.lastname: Choi
authors.forename: Byung Mu
authors.initials: BM
authors.lastname: Lee
authors.forename: Nam Deuk
authors.initials: ND
authors.lastname: Kim
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
authors.forename: Jee H
authors.initials: JH
authors.lastname: Jung
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000873:Anthracenes; D019253:Proto-Oncogene Proteins c-bcl-2; D004317:Doxorubicin; C034020:anthracene