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J Cell Mol Med. 2019 Aug 9. doi: 10.1111/jcmm.14523. [Epub ahead of print]

Synergistic combination of DT-13 and Topotecan inhibits aerobic glycolysis in human gastric carcinoma BGC-823 cells via NM IIA/EGFR/HK II axis.

Author information

1
Jiangsu Key Laboratory for Drug Screening, China Pharmaceutical University, Nanjing, China.
2
Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.
3
Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, China.
4
Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
5
School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, China.
6
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, Nanjing, China.
7
Tasly Research Institute, Tianjin Tasly Holding Group Co. Ltd., Tianjin, China.
8
Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China.

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.

KEYWORDS:

DT-13; EGFR; NM IIA; TPT; aerobic glycolysis; gastric cancer

PMID:
31397978
DOI:
10.1111/jcmm.14523
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