Thiazolidinediones (TZDs) act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPAR-gamma. The ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes. Following activation of PPAR-gamma, insulin resistance is decreased, adipocyte differentiation is modified, VEGF-induced angiogenesis is inhibited, leptin levels decrease (leading to an increased appetite), levels of certain interleukins (e.g. IL-6) fall, and adiponectin levels rise.
While TZDs have been approved for use in treating type II diabetes, some data has indicated that they possess weak anticancer activity. These compounds destroy cancer cells through dietary caloric restriction in a manner similar to the natural product-based energy restriction-mimetic agents (ERMAs) such as resveratrol and 2-deoxyglucose. In the current study, investigators at Ohio State University (Columbus, USA) sought to increase the anticancer activity of the TZDs, and to this end prepared the compound OSU-CG12, a derivative of the TZD ciglitazone.
They reported in the March 26, 2010, issue of the Journal of Biological Chemistry that when tested on cultures of breast or prostate cancer cells, OSU-CG12 was more than ten times more effective at killing cancer cells than either ciglitazone or resveratrol. Energy restrictions triggered by the drug resulted in the cancer cells dying from a combination of autophagy and apoptosis.
"Our study proves that this new agent kills cancer cells through energy restriction, said senior author Dr. Ching-Shih Chen, professor of medicinal chemistry, internal medicine and urology at Ohio State University. "This is important because it shows that it is possible to design drugs that target energy restriction, and it is exciting because energy-restricting mimetic agents may also be useful for other diseases, including metabolic syndromes, diabetes, cardiovascular disease, and obesity. Energy restriction may offer a powerful new strategy for treating cancer because it targets a survival mechanism used by many types of cancer.”
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