Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo
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Xiao-Wen Yu1, Sensen Lin2, Hong-Zhi Du1, Ren-Ping Zhao3, Shu-Yun Feng1, Bo-Yang Yu4, Lu-Yong Zhang1, Rui-Ming Li5, Chang-Min Qian5, Xue-Jun Luo5, Sheng-Tao Yuan1, Li Sun2
1Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China
2Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
3Department of Biophysics, University of Saarland, Homburg, Germany
4Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, Nanjing, China
5Tasly Research Institute, Tianjin Tasly Holding Group Co. Ltd., Tianjin, China
Sheng-Tao Yuan, e-mail: [email protected]
Li Sun, e-mail: [email protected]
Keywords: DT-13, topotecan, NM IIA, EGFR, gastric cancer
Received: October 10, 2015 Accepted: March 31, 2016 Published: April 20, 2016
Combination therapy has a higher success rate for many cancers compared to mono-therapy. The treatment of Topotecan (TPT) on gastric cancer (GC) is limited by its toxicity and the potential drug resistance. We found that the combination of the saponin monomer 13 from the dwarf lilyturf tuber (DT-13), performing anti-metastasis and anti-angiogenesis effects, with TPT synergistically induced apoptotic cytotoxicity in GCs with high EGF receptor (EGFR) expression, which was dependent on DT-13-induced endocytosis of EGFR. With TPT, DT-13 promoted EGFR ubiquitin--mediated degradation through myosin IIA-induced and Src/ caveolin-1 (Cav-1)-induced endocytosis of EGFR; inhibited EGFR downstream signalling and then increased the pro-apoptotic effects. Moreover, the synergistic pro-apoptotic efficacy of DT-13 and TPT in GCs with high EGFR expression was eliminated by both the NM II inhibitor (-)-blebbistatin and MYH-9 shRNA. The combination therapy of DT-13 with TPT showed stronger anti-tumour effects in vivo compared with their individual effects. Moreover, the results of combination therapy revealed selective upregulation of pro-apoptotic activity in TUNEL assays and cleaved caspase-3 and NM IIA in immunohischemical analysis; while specific downregulation of p-extracellular regulated kinase 1/2 (p-ERK1/2), EGFR and Cav-1 in immunohischemical analysis. Collectively, these findings have significant clinical implications for patients with tumours harbouring high EGFR expression due to the possible high sensitivity of this regimen.
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