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Zhu W, Ye L, Zhang J, et al. PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer. PLoS One. 2016;11(9):e0163768doi: 10.1371/journal.pone.0163768.
Zhu, W., Ye, L., Zhang, J., Yu, P., Wang, H., Ye, Z., & Tian, J. (2016). PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer. PloS one, 11(9), e0163768. https://doi.org/10.1371/journal.pone.0163768
Zhu, Wei, et al. "PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer." PloS one vol. 11,9 (2016): e0163768. doi: https://doi.org/10.1371/journal.pone.0163768
Zhu W, Ye L, Zhang J, Yu P, Wang H, Ye Z, Tian J. PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer. PLoS One. 2016 Sep 26;11(9):e0163768. doi: 10.1371/journal.pone.0163768. eCollection 2016. PMID: 27669567; PMCID: PMC5036843.
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PLoS One. 2016 Sep 26;11(9):e0163768. doi: 10.1371/journal.pone.0163768. eCollection 2016.

PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer.

PloS one

Wei Zhu, Liang Ye, Jianzhao Zhang, Pengfei Yu, Hongbo Wang, Zuguang Ye, Jingwei Tian

Affiliations

  1. School of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
  2. State Key Laboratory of Long-acting and Targeting Drug Delivery System, Non-clinical Research Department, Luye Pharma Group Ltd., Yantai, Shandong 264003, China.
  3. School of Pharmaceutical Sciences and Institute of Material Medical, Binzhou Medical University, Yantai, Shandong 264005, China.
  4. School of Pharmacy, Yantai University, Yantai, Shandong 264005, China.

PMID: 27669567 PMCID: PMC5036843 DOI: 10.1371/journal.pone.0163768

Abstract

PFKFB3 (6-phosphofructo-2-kinase) synthesizes fructose 2,6-bisphosphate (F2,6P2), which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting enzyme of glycolysis. Overexpression of the PFKFB3 enzyme leads to high glycolytic metabolism, which is required for cancer cells to survive in the harsh tumor microenvironment. The objective of this study was to investigate the antitumor activity of PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), a small molecule inhibitor of PFKFB3, against gastric cancer and to explore its potential mechanisms. The effects of PFK15 on proliferation, apoptosis and cell cycle progression in gastric cancer cells were evaluated by cytotoxicity and apoptosis assays, flow cytometry, and western blotting. In addition, the invasion inhibition effects of PFK15 were measured by transwell invasion assay and western blot analysis, and a xenograft tumor model was used to verify the therapeutic effect of PFK15 in vivo. Results showed that PFK15 inhibited the proliferation, caused cell cycle arrest in G0/G1 phase by blocking the Cyclin-CDKs/Rb/E2F signaling pathway, and induced apoptosis through mitochondria in gastric cancer cells. Tumor volume and weight were also significantly reduced upon intraperitoneal injection with PFK15 at 25 mg/kg. In addition, PFK15 inhibited the invasion of gastric cancer cells by downregulating focal adhesion kinase (FAK) expression and upregulating E-cadherin expression. Taken together, our findings indicate that PFK15 is a promising anticancer drug for treating gastric cancer.

Conflict of interest statement

The authors have declared that no competing interests exist. LY, JZZ, PFY and JWT are employees of Luye Pharma Group Ltd. There are no patents, products in development or marketed products to declare.

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