Synergistic combination of DT-13 and topotecan inhibits human gastric cancer via myosin IIA-induced endocytosis of EGF receptor in vitro and in vivo.
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.
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
Xiao-Wen
XW
Yu
Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Sensen
S
Lin
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
Hong-Zhi
HZ
Du
Department of Biophysics, University of Saarland, Homburg, Germany.
Ren-Ping
RP
Zhao
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
Shu-Yun
SY
Feng
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, Nanjing, China.
Bo-Yang
BY
Yu
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
Lu-Yong
LY
Zhang
Tasly Research Institute, Tianjin Tasly Holding Group Co. Ltd., Tianjin, China.
Rui-Ming
RM
Li
Tasly Research Institute, Tianjin Tasly Holding Group Co. Ltd., Tianjin, China.
Chang-Min
CM
Qian
Tasly Research Institute, Tianjin Tasly Holding Group Co. Ltd., Tianjin, China.
Xue-Jun
XJ
Luo
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
Sheng-Tao
ST
Yuan
Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Li
L
Sun
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004705:Endocytosis / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism*; D012503:Saponins / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019772:Topotecan / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D012503:Saponins; C578958:ruscogenin-1-O-(glucopyranosyl-(1-2))(xylopyranosyl-(1-3))fucopyranoside; D019772:Topotecan; C512478:EGFR protein, human; D066246:ErbB Receptors; D024507:Nonmuscle Myosin Type IIA
DT-13; EGFR; NM IIA; gastric cancer; topotecan