Troglitazone is an orally active agonist of the peroxisome proliferator-activated receptor γ (PPARγ), with EC50 values of 550nM and 780nM for human and murine receptors, respectively[1]. PPARγ is a widely expressed ligand-regulated transcription factor that controls the expression of genes involved in inflammation, redox balance, neurotrophic factor production, insulin sensitivity, and lipid and glucose metabolism[2]. By activating PPARγ, Troglitazone improves insulin resistance and regulates glucose and lipid metabolism, making it commonly used for the treatment of type II diabetes[3].
In vitro, treatment of mitochondria isolated from rat liver with Troglitazone (10, 50μM) for 5min induced mitochondrial swelling[4]. Treatment of C4-2 cells with Troglitazone (45μM) for 72h induced G0/G1 phase cell cycle arrest and increased the proportion of cells in the subG0 phase and the level of DNA fragmentation[5]. Treatment of human bladder cancer T24 and EJ cells with Troglitazone (25, 50μM) for 24h increased the ratio of light chain 3 (LC3)-II to actin in a time- and concentration-dependent manner[6].
In vivo, oral administration of Troglitazone (200mg/kg/day) for 5 weeks to male Balb/c mice bearing MIA Paca2 xenograft tumors significantly suppressed tumor growth without a significant effect on mouse body weight[7]. A single intraperitoneal injection of Troglitazone (300mg/kg) in female BALB/c mice significantly increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels after 6h, and this treatment induced pericentral hepatocyte necrosis within 24h[8].
References:
[1] WILSON T M, BROWN P J, STERNBACH D D, et al. The PPARs: from orphan receptors to drug discovery[J]. Journal of Medicinal Chemistry, 2000, 43(4): 527-550.
[2] CAI W, YANG T, LIU H, et al. Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair[J]. Progress in Neurobiology, 2018, 163: 27-58.
[3] PLOSKER G L, FAULDS D. Troglitazone: a review of its use in the management of type 2 diabetes mellitus[J]. Drugs, 1999, 57(3): 409-438.
[4] OKUDA T, NORIOKA M, SHITARA Y, et al. Multiple mechanisms underlying troglitazone-induced mitochondrial permeability transition[J]. Toxicology and Applied Pharmacology, 2010, 248(3): 242-248.
[5] AKINYEKE T O, STEWART L V. Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARγ-independent mechanism[J]. Cancer Biology & Therapy, 2011, 11(12): 1046-1058.
[6] YAN S, YANG X, CHEN T, et al. The PPARγ agonist Troglitazone induces autophagy, apoptosis and necroptosis in bladder cancer cells[J]. Cancer Gene Therapy, 2014, 21(5): 188-193.
[7] FUJITA M, HASEGAWA A, YAMAMORI M, et al. In vitro and in vivo cytotoxicity of troglitazone in pancreatic cancer[J]. Journal of Experimental & Clinical Cancer Research, 2017, 36(1): 91.
[8] JIA R, ODA S, TSUNEYAMA K, et al. Establishment of a mouse model of troglitazone-induced liver injury and analysis of its hepatotoxic mechanism[J]. Journal of Applied Toxicology, 2019, 39(11): 1541-1556.