Open AccessSynergistic combination of DT‐13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC‐823 cells via NM IIA/EGFR/HK II axis
Author(s) -
Yu XiaoWen,
Wei Dandan,
Gao YingSheng,
Du HongZhi,
Yu BoYang,
Li RuiMing,
Qian ChangMin,
Luo XueJun,
Yuan ShengTao,
Wang JunSong,
Sun Li
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14523
Subject(s) - anaerobic glycolysis , chemistry , glycolysis , pharmacology , in vivo , chemosensitizer , cancer research , egfr inhibitors , epidermal growth factor receptor , combination therapy , hexokinase , in vitro , biochemistry , receptor , medicine , enzyme , biology , cytotoxicity , microbiology and biotechnology
Abstract DT‐13 combined with topotecan (TPT) showed stronger antitumour effects in mice subcutaneous xenograft model compared with their individual effects in our previous research. Here, we further observed the synergistically effect in mice orthotopic xenograft model. Metabolomics analysis showed DT‐13 combined with TPT alleviated metabolic disorders induced by tumour and synergistically inhibited the activity of the aerobic glycolysis‐related enzymes in vivo and in vitro. Mechanistic studies revealed that the combination treatment promoted epidermal growth factor receptor (EGFR) degradation through non‐muscle myosin IIA (NM IIA)‐induced endocytosis of EGFR, further inhibited the activity of hexokinase II (HK II), and eventually promoted the aerobic glycolysis inhibition activity more efficiently compared with TPT or DT‐13 monotherapy. The combination therapy also inhibited the specific binding of HK II to mitochondria. When using the NM II inhibitor (‐)002Dblebbistatin or MYH‐9 shRNA, the synergistic inhibition effect of DT‐13 and TPT on aerobic glycolysis was eliminated in BGC‐823 cells. Immunohistochemical analysis revealed selective up‐regulation of NM IIA while specific down‐regulation of p‐CREB, EGFR, and HK II by the combination therapy. Collectively, these findings suggested that this regimen has significant clinical implications, warranted further investigation.