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

De,Umasankar; Chun,Pusoon; Choi,Wahn Soo; Lee,Byung Mu; Kim,Nam Deuk; Moon,Hyung Ryong; Jung,Jee H.; Kim,Hyung Sik

doi:10.3892/ijo.2013.2160

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

Authors:
- Umasankar De
- Pusoon Chun
- Wahn Soo Choi
- Byung Mu Lee
- Nam Deuk Kim
- Hyung Ryong Moon
- Jee H. Jung
- Hyung Sik Kim
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Affiliations: College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea, College of Pharmacy, Inje University, Gyeongnam 621-749, Republic of Korea, Institute of Biomedical Science and Technology, College of Medicine, Konkuk University, Chungju 380-701, Republic of Korea, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
Published online on: October 31, 2013 https://doi.org/10.3892/ijo.2013.2160
Pages: 167-176

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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.

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