Diabetes Drug Inhibits Insulin-like Growth Factor-I Promoted Skin Tumors

John DiGiovanni, Ph.D.
University of Texas M.D. Anderson Cancer Center
P30ES07784

Background: Thiazolidinediones are a new class of drugs for the treatment of type 2 or insulin-dependent diabetes. They act by improving insulin sensitivity (the capacity of cells to respond to insulin-stimulated glucose uptake) in fat tissue, liver, and skeletal muscle. The class of drugs includes rosiglitazone, troglitazone and pioglitazone. Thiazolidinediones consistently lower glucose concentrations as well as free fatty acid concentrations in clinical studies. Insulin concentrations also decrease in most studies. Such changes indicate that thiazolidinediones act as insulin sensitizers, which has been confirmed by direct measurements in studies in humans. For example, treatment of non-diabetic subjects or those with type 2 diabetes for three to six months with troglitazone, rosiglitazone, or pioglitazone increases insulin-stimulated glucose uptake in peripheral tissues. In similar studies, thiazolidinediones increase liver insulin sensitivity and insulin sensitivity in adipose tissue. In addition, thiazolidinediones have recently been shown to stem tumor development. However, the molecular mechanisms for this finding have, until now, been unknown.

Advance: This team of NIEHS-supported investigators has shown that rosiglitazone and troglitazone inhibit insulin-like growth factor-I (IGF-I)-promoted skin tumor development by 73% in a transgenic mouse strain. IGF-I is a growth factor structurally related to insulin and it is the primary protein involved in responses of cells to growth hormone. These results were somewhat surprising because previous studies have reported that these drugs are ineffective in inhibiting UV- or chemically-induced mouse skin cancers. The molecular mechanisms involved in the IFG-I inhibition are due to activation of AMP-activated protein kinase and inhibition of p70S6 kinase.

Implications: These studies show possible mechanisms for the anti-carcinogenic activity of thiazolidinediones. Insulin resistance, the cause of type-2 diabetes and other metabolic disorders, is associated with an increased risk of tumor development which is believed to be caused by an increase in IGF-I activity. These findings show that thiazolidinediones are capable of directly inhibiting the tumor-promoting activity of IGF-I and may provide additional benefits to type-2 diabetic patients by reducing their risk of cancer.

Citation: He G, Sung YM, DiGiovanni J, Fischer SM. Thiazolidinediones inhibit insulin-like growth factor-I-induced activation of p70S6 kinase and suppress insulin-like growth factor-I tumor-promoting activity. Cancer Res. 2006 Feb 1;66(3):1873-8.