3PO inhibits recombinant PFKFB3 activity with IC50 of 25 μM, suppresses glucose uptake, and decreases the intracellular concentration of Fru-2,6-BP, lactate, ATP, NAD+, and NADH in vitro.
3PO is a potent PFKFB3 inhibitor with Ki value of 25μM. It suppressed glycolytic flux and was cytostatic to neoplastic cells. 3PO inhibited recombinant PFKFB3 activity, suppressed glucose uptake, and decreased the intracellular concentration of Fru-2,6-BP, lactate, ATP, NAD+, and NADH. 3PO markedly attenuated the proliferation of several human malignant hematopoietic and adenocarcinoma cell lines with IC50 values ranging in 1.4-24μM and is selectively cytostatic to ras-transformed human bronchial epithelial cells relative to normal human bronchial epithelial cells. Intraperitoneal administration of 3PO at dose of 70mg/kg to tumor-bearing mice suppressed growth of tumor xenografts, including Lewis lung carcinoma, MDA-MB231 and HL-60, as well as markedly reduced the intracellular concentration of Fru-2,6-BP, glucose uptake, and growth of established tumors in vivo[3]. Blockade of PFKFB3 by 3PO reduced vessel sprouting in endothelial cell (EC) spheroids, zebrafish embryos, and the postnatal mouse retina by inhibiting EC proliferation and migration. Also it suppressed vascular hyperbranching induced by inhibition of Notch or VEGFR1 and amplified the antiangiogenic effect of VEGF blockade[4].
作用机制
3PO may bind the Fru-6-P binding site and inhibit PFKFB3 through a mixed inhibition mechanism in both competitive and uncompetitive manner.[3]
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