Hsp90 Inhibitor Geldanamycin Enhances the Antitumor Efficacy of Enediyne Lidamycin in Association with Reduced DNA Damage Repair

Han, Fei-Fei; Li, Liang; Shang, Bo-Yang; Shao, Rong-Guang; Zhen, Yong-Su

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저자정보: Han, Fei-Fei (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) Li, Liang (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) Shang, Bo-Yang (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) Shao, Rong-Guang (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College) Zhen, Yong-Su (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College)

저널정보: 아시아태평양암예방학회 Asian Pacific journal of cancer prevention : APJCP Asian Pacific journal of cancer prevention : APJCP 제15권 제17호

발행연도: 2014.1

수록면: 7,043 - 7,048 (6page)

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Inhibition of heat shock protein 90 (Hsp90) leads to inappropriate processing of proteins involved in DNA damage repair pathways after DNA damage and may enhance tumor cell radio- and chemotherapy sensitivity. To investigate the potentiation of antitumor efficacy of lidamycin (LDM), an enediyne agent by the Hsp90 inhibitorgeldanamycin (GDM), and possible mechanisms, we have determined effects on ovarian cancer SKOV-3, hepatoma Bel-7402 and HepG2 cells by MTT assay, apoptosis assay, and cell cycle analysis. DNA damage was investigated with H2AX C-terminal phosphorylation (${\gamma}H2AX$) assays. We found that GDM synergistically sensitized SKOV-3 and Bel-7402 cells to the enediyne LDM, and this was accompanied by increased apoptosis. GDM pretreatment resulted in a greater LDM-induced DNA damage and reduced DNA repair as compared with LDM alone. However, in HepG2 cells GDM did not show significant sensitizing effects both in MTT assay and in DNA damage repair. Abrogation of LDM-induced $G_2/M$ arrest by GDM was found in SKOV-3 but not in HepG2 cells. Furthermore, the expression of ATM, related to DNA damage repair responses, was also decreased by GDM in SKOV-3 and Bel-7402 cells but not in HepG2 cells. These results demonstrate that Hsp90 inhibitors may potentiate the antitumor efficacy of LDM, possibly by reducing the repair of LDM-induced DNA damage.

#Geldanamycin #DNA damage repair #lidamycin #enediyne #ATRIP

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Han, Fei-Fei

소속기관 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical C