Oncotarget

Research Papers:

HSP90 inhibitor 17-DMAG exerts anticancer effects against gastric cancer cells principally by altering oxidant-antioxidant balance

Jeong Goo Kim, Sang Chul Lee, Ok-Hee Kim, Kee-Hwan Kim, Kyo Young Song, Sang Kuon Lee, Byung Jo Choi, Wonjun Jeong and Say-June Kim _

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Oncotarget. 2017; 8:56473-56489. https://doi.org/10.18632/oncotarget.17007

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Abstract

Jeong Goo Kim1, Sang Chul Lee1, Ok-Hee Kim1, Kee-Hwan Kim1, Kyo Young Song2, Sang Kuon Lee1, Byung Jo Choi1, Wonjun Jeong1 and Say-June Kim1

1Department of Surgery, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

2Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Correspondence to:

Say-June Kim, email: [email protected]

Keywords: 17-DMAG, antioxidant enzymes, HSP90 inhibitor, reactive oxygen species, stomach cancer

Received: May 26, 2016    Accepted: March 07, 2017    Published: April 10, 2017

ABSTRACT

Heat shock protein 90 (HSP90) stabilizes numerous oncoproteins and, therefore, its inhibition has emerged as a promising antineoplastic strategy for diverse malignancies. In this study, we determined the therapeutic effects and mechanisms of action of a specific HSP90 inhibitor, 17-dimethylamino-ethylamino-17-demethoxygeldanamycin (17-DMAG), in gastric cancer cell lines (AGS, SNU-1, and KATO-III), patient-derived tissues, and a mouse xenograft model. 17-DMAG exerted anticancer effects against gastric cancer cells, manifested by significantly decreased proliferation rates (P < 0.05) and increased expression of apoptotic markers. Flow cytometry using dichlorofluorescein (DCF) diacetate revealed that 17-DMAG dose-dependently increases reactive oxygen species (ROS) levels in gastric cancer cells. Inhibition of ROS by N-acetyl-L-cysteine (NAC) abrogated the proapoptotic effects of 17-DMAG, as demonstrated by the decreased expression of proapoptotic proteins. In addition, 17-DMAG dose- and time-dependently reduced the expression of antioxidants such as catalase and glutathione peroxidase (GPx). Moreover, 17-DMAG reduced the expression of nuclear respiratory factor (NRF)-1 and NRF-2, and prevented them from migrating from the cytoplasm to the nucleus dose-dependently. Finally, in a nude mouse xenograft model, the shrinkage of tumors was more prominent in mice treated with 17-DMAG than in control mice (P < 0.05). Taken altogether, our results suggest that 17-DMAG exerts potent antineoplastic activity against gastric cancer cells primarily by promoting ROS generation and suppressing antioxidant enzyme activities.


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