Troglitazone

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.

Troglitazone是一种具有口服活性的过氧化物酶体增殖物激活受体γ（PPARγ）激动剂，对人和鼠的EC₅₀值分别为550nM和780nM^[1]。PPARγ是一种广泛表达的配体调节转录因子，控制参与炎症、氧化还原平衡、营养因子产生、胰岛素敏感性以及脂质和葡萄糖代谢的基因表达^[2]。Troglitazone通过激活PPARγ，改善胰岛素抵抗和调节糖脂代谢，通常用于II型糖尿病的治疗^[3]。

在体外，Troglitazone（10, 50μM）处理大鼠肝脏分离的线粒体5min，诱导了线粒体肿胀^[4]。Troglitazone（45μM）处理C4-2细胞72h，诱导了G₀/G₁期细胞周期阻滞，并增加了subG₀期细胞比例和DNA碎片化水平^[5]。Troglitazone（25, 50μM）处理人膀胱癌T24和EJ细胞24h，以时间和浓度依赖性的方式增加了轻链3（LC3）-II与肌动蛋白的比率^[6]。

在体内，Troglitazone（200mg/kg/day）通过口服处理携带MIA Paca2异种移植瘤的Balb/c雄性小鼠5周，显著抑制了肿瘤的生长，且对小鼠体重无显著影响^[7]。Troglitazone（300mg/kg）通过单次腹腔注射处理雌性BALB/c小鼠6h，显著升高了血浆丙氨酸氨基转移酶（ALT）和天门冬氨酸氨基转移酶（AST）水平，该处理在24h后可诱导中央静脉周围的肝细胞坏死^[8]。