PPARgamma agonists can be expected to potentiate the efficacy of metronomic chemotherapy through CD36 up-regulation

Abstract

The ability of metronomic chemotherapy to induce endothelial apoptosis has been traced to increased endothelial expression of thrombospondin-1, which activates endothelial CD36 receptors, triggering the extrinsic apoptotic pathway. Endothelial expression of CD36 is variable. Recent studies show that PPAR gamma agonists - previously shown to have angiostatic activity - can markedly boost endothelial expression of CD36, thereby potentiating the apoptotic response of endothelial cells to thrombospondin-1-mimetic peptides. Thus, concurrent administration of PPAR gamma agonists would be expected to enhance the efficacy of metronomic chemotherapy. These considerations may help to rationalize recent reports that a regimen consisting of low-dose trofosfamide, pioglitazone, and a cox-2 inhibitor achieves tumor regression or prolonged tumor stasis in a meaningful proportion of cancer patients. The angiostatic efficacy of metronomic chemotherapy complemented by PPAR gamma agonist administration would likely be potentiated by ancillary measures that block the survival signals evoked by endothelial growth factors such as VEGF or angiopoietin-1.