Tunicamycin enhances the antitumor activity of trastuzumab on breast cancer in vitro and in vivo
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Xiqian Han1,*, Xiaobing Zhang1,*, Hui Li1,*, Shengshi Huang1, Shu Zhang1, Fengshan Wang1, Yikang Shi1
1National Glycoengineering Research Center, School of Pharmaceutical Science, Shandong University, Jinan, China
*These authors have contributed equally to this work
Yikang Shi, e-mail: [email protected]
Keywords: trastuzumab, tunicamycin, breast cancer
Received: May 25, 2015 Accepted: August 26, 2015 Published: October 12, 2015
Trastuzumab, a humanized monoclonal antibody targeting HER2, has demonstrated clinical benefits for women with HER2-positive breast cancer; however, trastuzumab resistance remains the biggest clinical challenge. In this study, results showed that tunicamycin, an inhibitor of N-glycosylation, synergistically enhanced the antitumor activity of trastuzumab against HER2-overexpressing breast cancer cells through induction of cell cycle arrest and apoptosis. Combined treatment of tunicamycin with trastuzumab dramatically decreased the expression of EGFR family and its down signaling pathway in SKBR3 and MCF-7/HER2 cells. Tunicamycin dose-dependently inhibited tumor growth in both of SKBR3 xenografts and MCF-7/HER2 xenografts. Optimal tunicamycin without inducing ER stress in liver tissue significantly increased the antitumor effect of trastuzumab in MCF-7/HER2 xenografts. Combinations of trastuzumab with N-glycosylation inhibitors tunicamycin may be a promising approach for improving clinical efficacy of trastuzumab.
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