Abstract 3363: Inhibition of glycolysis and proliferation of colon cancer cells by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) an inhibitor of 6-phosphofructo-2-kinase (PFKFB3)

Abstract

In human colon cancer cells, glycolytic activity shows a positive correlation with proliferation. PFKFB3 is an important enzyme regulating glycolysis in many tumor cells. We have studied the action of an established inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) as a single agent and in combination with other molecules that affect glycolysis and proliferation in four colon cancer cell lines (Caco-2, HCT116, HT29 and SW1116). Glucose uptake and cell proliferation were inhibited by 3PO and butyrate and additive effects were seen with 10 µM 3PO and 1 mM butyrate. Induction of alkaline phosphatase activity serves as a marker of differentiation in colon cancer cells. The large induction of alkaline phosphatase activity by butyrate seen in most colon cancer cell lines was not observed with 3PO. Similar contrasting effects on induction of alkaline phosphatase activity were seen with rat Morris hepatoma 7777 cells where 2-3 fold induction was seen with 1 µM vorinostat or 1 mM butyrate but no significant effect was seen with 3PO in the range of 5-30 µM. The biguanides, metformin and phenformin, increase glycolysis but inhibit proliferation of colon cancer cells. After combination treatment with 3PO, glycolysis was inhibited, as judged by glucose uptake and acidification of the medium, and additive inhibitory effects on cell proliferation could be observed. For example, after a 72 hour incubation of Caco-2 cells with 10 µM 3PO, 25 µM phenformin or 1 mM metformin, as single agents, proliferation relative to controls was decreased 20%, 17% and 34%, respectively. For combinations of 3PO and phenformin or 3PO and metformin the decreases relative to controls were 48% and 58%, respectively. In conclusion, 3PO was an inhibitor of proliferation of colon cancer cells, especially the rapidly growing HCT116 and HT29 cell lines. 3PO may be a useful agent in combination with other drugs that inhibit colon cancer cell proliferation. Citation Format: Michael A. Lea, Raymond Geherty, Rachelle David, Charles desBordes. Inhibition of glycolysis and proliferation of colon cancer cells by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) an inhibitor of 6-phosphofructo-2-kinase (PFKFB3). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3363. doi:10.1158/1538-7445.AM2014-3363

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“…The formation of NETs is strictly dependent on exogenous glucose and glycolysis 48 and the release of ETs has also been associated with glycolysis 29,33,50 . In the present study, we found that inhibiting glycolysis with 3PO reduces the uptake of 2‐deoxyglucose and the secretion of PFKFB3, a glycolytic enzyme activator 51,52 . STF‐31, a GLUT1 inhibitor, blocks glucose uptake and induces the apoptosis of GLUT1 myeloma cells 53 .…”

“…29,33,50 In the present study, we found that inhibiting glycolysis with 3PO reduces the uptake of 2-deoxyglucose and the secretion of PFKFB3, a glycolytic enzyme activator. 51,52 STF-31, a GLUT1 inhibitor, blocks glucose uptake and induces the apoptosis of GLUT1 myeloma cells. 53 Azd3965 inhibits the transport of lactic acid, promoting the accumulation of intermediate products during glycolysis.…”

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“…Wang et al [74] recently demonstrated the use of HK2 as a single-cell sequencing-validated cellular marker for the high-throughput screening of highly glycolytic exfoliated UBC cells in urine, a method that showed sensitivity, specificity, positive predictive value, and negative predictive value superior to that of urinary cytology, accurately detecting BC before this standard method. A few preclinical reports have shown that the chemical inhibition of HK2 impaired the glycolytic activity of UBC cells by lowering glucose consumption and lactate production [75] and reduced the UBC cells' viability [76]. HK2 has been described as a crucial mediator of glycolytic activity in BC promoted by the long non-coding RNA UCA-1 [77,78]; additionally, the microRNA-21 inhibition in UBC cell lines resulted in decreased glycolytic activity, as seen by the reduced HK2 activity [72], which highlights the importance of epigenetic modifications in the UBC cells' metabolism.…”

“…This non-metabolizable glucose analogue has been widely used in preclinical assays, with promising results [85,86]. In BC specifically, proliferation was inhibited upon 2DG treatment in eight BC cell lines, and an additive effect was obtained with the coadministration of a PFK-related enzyme inhibitor [76]. 2DG markedly inhibited the UBC cells' viability, proliferation, lactate production, migration, invasion, and cell cycle progression and promoted cell death by apoptosis and necrosis in our "in vitro" experiments.…”

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“…Unfortunately, this reagent has no inhibitory activity on the phosphorylation of fructose 6-phosphate and is nonspecific for PFK2 483 . The researchers designed and synthesized the PFKFB3 inhibitor 3PO based on the homologous model of PFKFB3 isozyme 484 , which has good anti-cancer activity in various types of tumor cells 485 , 486 , 487 . Due to the poor pharmacokinetic characteristics and low efficacy of 3PO 488 , subsequent researchers have improved its efficacy by loading nanocarriers into multiple types of cells 489 .…”