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

View Article: PubMed Central - PubMed

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.

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Related in: MedlinePlus

PFK15 suppressed tumor growth in gastric tumor xenograft models.MKN45 tumor-bearing mice were treated with PFK15 intraperitoneally at 25 mg/kg or vehicle every three days for 15 days. PFK15 had satisfactory inhibition effects against MKN45 tumor growth with an IR of 56.10% compared with vehicle group (a). Tumor volumes and body weight were measured twice a week (b, c). Columns, mean; bars, SD. *p<0.05, compared with vehicle controls.
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pone.0163768.g007: PFK15 suppressed tumor growth in gastric tumor xenograft models.MKN45 tumor-bearing mice were treated with PFK15 intraperitoneally at 25 mg/kg or vehicle every three days for 15 days. PFK15 had satisfactory inhibition effects against MKN45 tumor growth with an IR of 56.10% compared with vehicle group (a). Tumor volumes and body weight were measured twice a week (b, c). Columns, mean; bars, SD. *p<0.05, compared with vehicle controls.

Mentions: To investigate the in vivo effects of PFK15 on gastric tumor growth we intraperitoneally injected mice bearing 120 mm3 tumors at 25 mg/kg or vehicle (SCMC) every three days for 15 days, according to Clem’s report [14]. PFK15 significantly inhibited tumor volume and tumor weight (IR, 56.10%) in a MKN45 xenograft model without a major effect on body mass (Fig 7a, 7b and 7c). Moreover, all the animals survived at the end of the treatment, suggesting limited toxicity. These data suggested that PFK15 could effectively suppress gastric tumor growth with no obvious side effects.


PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer
PFK15 suppressed tumor growth in gastric tumor xenograft models.MKN45 tumor-bearing mice were treated with PFK15 intraperitoneally at 25 mg/kg or vehicle every three days for 15 days. PFK15 had satisfactory inhibition effects against MKN45 tumor growth with an IR of 56.10% compared with vehicle group (a). Tumor volumes and body weight were measured twice a week (b, c). Columns, mean; bars, SD. *p<0.05, compared with vehicle controls.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5036843&req=5

pone.0163768.g007: PFK15 suppressed tumor growth in gastric tumor xenograft models.MKN45 tumor-bearing mice were treated with PFK15 intraperitoneally at 25 mg/kg or vehicle every three days for 15 days. PFK15 had satisfactory inhibition effects against MKN45 tumor growth with an IR of 56.10% compared with vehicle group (a). Tumor volumes and body weight were measured twice a week (b, c). Columns, mean; bars, SD. *p<0.05, compared with vehicle controls.
Mentions: To investigate the in vivo effects of PFK15 on gastric tumor growth we intraperitoneally injected mice bearing 120 mm3 tumors at 25 mg/kg or vehicle (SCMC) every three days for 15 days, according to Clem’s report [14]. PFK15 significantly inhibited tumor volume and tumor weight (IR, 56.10%) in a MKN45 xenograft model without a major effect on body mass (Fig 7a, 7b and 7c). Moreover, all the animals survived at the end of the treatment, suggesting limited toxicity. These data suggested that PFK15 could effectively suppress gastric tumor growth with no obvious side effects.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus