Reprofiling of Troglitazone Towards More Active and Less Toxic Derivatives: A New Hope for Cancer Treatment?

Abstract

The existence of unresponsive tumors and the appearance of resistant tumors during the course of treatments both justify that we increase urgently the panel of pharmacological molecules able to fight cancer. An interesting strategy is drug reprofiling (also known as drug repositioning, drug repurposing or drug retasking) that consists of identifying and developing new uses for existing drugs. This review illustrates drug reprofiling with troglitazone (TGZ), a synthetic PPARγ agonist initially used for the treatment of type II diabetes. The fact that TGZ also displays anticancer effects is known since the end of the nineties but its development as an anticancer agent was slowed down due to hepatotoxic side effects. Part of the knowledge available for TGZ, mainly the molecular basis for PPARγ activation, its metabolization pathways and the side effects on hepatocytes, were taken into account to elaborate new molecules. Key findings were that unsaturated TGZ derivatives, when compared to TGZ, do not activate PPARγ, exhibit a higher efficiency on cancer cells and a lower toxicity towards hepatocytes. However, a weakness is that the mechanisms involved in the anticancer effects are still not completely understood and that the efficiency of such derivatives has not yet been completely studied in vivo. Data about this point should become available very soon from animal models and this will be a prerequisite to initiate clinical trials with these potential new anticancer drugs developed from a drug repurposing strategy.

New desulfured troglitazone derivatives: Improved synthesis and biological evaluation

“…Compounds bearing this moiety were recently proved to be of high interest as they exhibited numerous biological activities [7][8][9][10][11] and many of them showed promising in vitro and in vivo anticancerous properties. In particular, our team developed [12][13][14] Structure-Activity Relationships (SAR) studies starting from the structure of troglitazone (TGZ) (Figure 1), a molecule formerly used as an antidiabetic. We showed that some structural features both increased the antiproliferative activity toward breast cancer cell lines and decreased the toxicity against primary cultured non-malignant human hepatocytes.…”

Cell cycle synchronisation using thiazolidinediones affects cellular glucose metabolism and enhances the therapeutic effect of 2-deoxyglucose in colon cancer

“…Troglitazone and pioglitazone are antidiabetic drugs, although troglitazone was withdrawn from the antidiabetic market due to hepatotoxicity. Recently, the strategy for reprofiling drug with troglitazone has been tried; unsaturated troglitazone derivatives exhibit a higher efficiency for cancer cells and a lower toxicity towards hepatocytes than troglitazone 16 . In this study, both troglitazone and pioglitazone induced cell cycle arrest at G1 phase, which increased 2-DG uptake in cancer cells and augmented its therapeutic efficacy.…”

Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor

“…Finally, Strategy C afforded the most potent PPAR-γ agonists, but none of them behaved as an ARB. It is well-known that many PPAR-γ activating compounds exhibit anti-proliferative activity [46][47][48][49][50]. Thus, it could be interesting to determine if our dual molecules also display anti-proliferative activity.…”

“…All these active molecules contained an imidazole heterocycle. Triazole derivatives from strategy B (44,45,50), or chromane-containing troglitazone analogs from strategy C (54, 57) did not exhibit any activity. After this first sorting, the active molecules (5-39) were selected in order to check their potency at various concentrations, thus giving access to their IC 50 .…”