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A New Histone Deacetylase Inhibitor, MHY4381, Induces Apoptosis via Generation of Reactive Oxygen Species in Human Prostate Cancer Cells

Biomolecules & Therapeutics 2020년 28권 2호 p.184 ~ 194
 ( Richa Sachan ) - Sungkyunkwan University School of Pharmacy

 ( Dey Prasanta ) - Sungkyunkwan University School of Pharmacy
 ( Park Cha-Eun ) - Pusan National University College of Pharmacy
 ( Yang Jung-Ho ) - Pusan National University College of Pharmacy
손지연 ( Son Ji-Yeon ) - Sungkyunkwan University School of Pharmacy
 ( Park Jae-Hyeon ) - Sungkyunkwan University School of Pharmacy
 ( Lee Su-Hyun ) - Sungkyunkwan University School of Pharmacy
안미영 ( Ahn Mee-Young ) - Silla University College of Medical and Life Sciences Division of Bioindustry
김인수 ( Kim In-Su ) - Sungkyunkwan University School of Pharmacy
문형룡 ( Moon Hyung-Ryong ) - Pusan National University College of Pharmacy
김형식 ( Kim Hyung-Sik ) - Sungkyunkwan University School of Pharmacy

Abstract


Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents, which can be used to inhibit cell proliferation and induce apoptosis in several types of cancer cells. In this study, we investigated the anticancer activity of MHY4381, a newly synthesized HDAC inhibitor, against human prostate cancer cell lines and compared its efficacy with that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor. We assessed cell viability, apoptosis, cell cycle regulation, and other biological effects in the prostate cancer cells. We also evaluated a possible mechanism of MHY4381 on the apoptotic cell death pathway. The IC50 value of MHY4381 was lower in DU145 cells (IC50=0.31 μM) than in LNCaP (IC50=0.85 μM) and PC-3 cells (IC50=5.23 μM). In addition, the IC50 values of MHY4381 measured in this assay were significantly lower than those of SAHA against prostate cancer cell lines. MHY4381 increased the levels of acetylated histones H3 and H4 and reduced the expression of HDAC proteins in the prostate cancer cell lines. MHY4381 increased G2/M phase arrest in DU145 cells, and G1 arrest in LNCaP cells. It also activated reactive oxygen species (ROS) generation, which induced apoptosis in the DU145 and LNCaP cells by increasing the ratio of Bax/Bcl-2 and releasing cytochrome c into the cytoplasm. Our results indicated that MHY4381 preferentially results in antitumor effects in DU145 and LNCaP cells via mitochondria-mediated apoptosis and ROS-facilitated cell death pathway, and therefore can be used as a promising prostate cancer therapeutic.

키워드

HDAC inhibitor; MHY4381; Prostate cancer; Apoptosis; Reactive oxygen species
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