Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity.
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 gamma 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-D-glucose 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 [18F]2-deoxyglucose (FDG) positron emission tomography showed that pioglitazone increases FDG accumulation by normal tissue but does not significantly alter FDG uptake by A-549 xenografts. Thus, peroxisome proliferator-activated receptor gamma agonists may be useful in overcoming the increase in blood glucose caused by inhibitors of PI3K signaling by preventing the inhibition of normal tissue insulin-mediated glucose uptake without affecting antitumor activity.
Ihle
Nathan T
NT
The University of Texas M. D. Anderson Cancer Center, FC-6.3044, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Lemos
Robert
R
Schwartz
David
D
Oh
Junghwan
J
Halter
Robert J
RJ
Wipf
Peter
P
Kirkpatrick
Lynn
L
Powis
Garth
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives / Q000378:metabolism; D006067:Gonanes / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology* / Q000517:prevention & control*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051246:Glucose Transport Proteins, Facilitative; D006067:Gonanes; D047495:PPAR gamma; C496788:PX-866; D045162:Thiazolidinediones; C047515:2-fluoro-2-deoxyglucose-6-phosphate; D019298:Glucose-6-Phosphate; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose; D000077205:Pioglitazone