Peroxisome proliferator-activated receptor γ agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity

Abstract

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade is an important component of the insulin signaling in normal tissues leading to glucose uptake and homeostasis and for cell survival signaling in cancer cells. Hyperglycemia is an on-target side effect of many inhibitors of PI3K/Akt signaling including the specific PI3K inhibitor PX-866. The peroxisome proliferator-activated receptor ; agonist pioglitazone, used to treat type 2 diabetes, prevents a decrease in glucose tolerance caused by acute administration of PX-866. Our studies have shown that pioglitazone does not inhibit the antitumor activity of PX-866 in A-549 non-small cell lung cancer and HT-29 colon cancer xenografts. In vitro studies also showed that pioglitazone increases 2-[1-14 C]deoxy-Dglucose uptake in L-6 muscle cells and prevents inhibition of 2-deoxyglucose uptake by PX-866. Neither pioglitazone nor PX-866 had an effect on 2-deoxyglucose uptake in A-549 lung cancer cells. In vivo imaging studies using [ 18

Exploiting tumor metabolism for non-invasive imaging of the therapeutic activity of molecularly targeted anticancer agents

“…59 Consistent with this anti-glycolytic effect, PI3K inhibition with PX-866 in a lung carcinoma model, or everolimus in a gastrointestinal stromal tumor model, caused a decline in FDG uptake as detected by PET imaging. 60,61 More importantly, this effect has also been seen in patients during clinical trials with mTOR inhibitors.…”

“…Despite the fact that it is not specific for any of the therapies described above, the change in 13 C-MRS measured 13 C-pyruvate-lactate exchange could nevertheless have potential as a promising PD biomarker for the anticancer activity of these agents. Pi3K-AKT-mTOr inhibitors (LY294002, wortmannin, Pi-103, PX-866, everolimus) (-)PC, (-)total choline (cells), 51,57,58 (-)pyruvate-lactate exchange (cells and tumor xenografts, DNP analysis) 59 (-)FDG uptake (tumor xenografts) 60 The signs (+) and (-) signify an increase and a decrease in metabolite levels, respectively. P MRS) has been used clinically to assess metabolism in cancer tissues such as the breast, brain and prostate at baseline and following treatment with cytotoxic drugs and radiotherapy.…”

Cancer-drug induced insulin resistance: Innocent bystander or unusual suspect

“…It has been shown, in vitro, that chronic treatment of pancreatic islet cells with the PI3K-inhibitor PIK-75 reduced insulin secretion suggesting an effect on beta-cell function rather than insulin resistance [57]. However, PI3K inhibition using the small molecule inhibitor PX-866 reduces glucose uptake in isolated muscle cells suggesting effects on insulin sensitivity [58].…”

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…Recent findings have shown ways to circumvent this problem. Pioglitazone, which is a peroxisome proliferator-activated receptor gamma agonist, prevents the hyperglycemia caused by PX-866 without affecting its antitumor activity [66] . PX-866 had entered phase I clinical trials in 2008 and is currently in phase II clinical trials for prostate cancer treatment.…”