Abstract

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.

Highlights

  • Gastric cancer (GC) remains a major health issue and a leading cause of death worldwide

  • 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 gastric cancer (GC) with high EGF receptor (EGFR) expression, which was dependent on DT-13-induced endocytosis of EGFR

  • DT-13 combined with TPT had a synergistic anti-cancer effect on GCs with high EGFR expression

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Summary

Introduction

Gastric cancer (GC) remains a major health issue and a leading cause of death worldwide. The incidence of GC worldwide has been decreasing in recent years, but it remains the fourth most common malignant tumour and performs the second highest mortality rate of the cancerous diseases [1]. An increasing number of GC targets have been found, including EGFR, HER2 and VEGF [2]; several studies have demonstrated that the high expression of EGFR in GC has a close relationship with its occurrence, development and biological behaviour [3]. Aichler M et al reported that high EGFR expression induced chemoresistance and was correlated with a poor prognosis in the clinic [4, 5]. As taking the advantage of combination therapies (i.e., avoiding the risk of the development of resistance, increasing the effectiveness of the therapy, and the effectiveness of clinical combination therapies with TPT), we designed DT-13 combined with TPT, to increase the expression of NM IIA and increase the effectiveness of TPT therapy for GCs

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