TY - JOUR T1 - Induction of Apoptosis in Renal Tubular Cells by Histone Deacetylase Inhibitors, a Family of Anticancer Agents JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 978 LP - 984 DO - 10.1124/jpet.108.137398 VL - 325 IS - 3 AU - Guie Dong AU - Lysa Wang AU - Cong-Yi Wang AU - Tianxin Yang AU - M. Vijay Kumar AU - Zheng Dong Y1 - 2008/06/01 UR - http://jpet.aspetjournals.org/content/325/3/978.abstract N2 - Inhibitors of histone deacetylases, including suberoylanilide hydroxamic acid (SAHA) and Trichostatin A, are a new class of anticancer agents. With potent chemotherapy effects in cancers, these agents are not obviously toxic in normal nonmalignant cells or tissues. However, their toxicity in kidney cells has not been carefully evaluated. Here, we demonstrate a potent apoptosis-inducing activity of SAHA in cultured renal proximal tubular cells. SAHA induces apoptosis at low micromolar concentrations. At 5 μM, SAHA induces 30 to ∼40% apoptosis in 18 h. The apoptosis is accompanied by notable caspase activation; however, the general caspase inhibitor VAD can only partially suppress SAHA-induced apoptosis, suggesting the involvement of both caspase-dependent and -independent mechanisms. SAHA treatment leads to cytochrome c release from mitochondria, which is suppressed by Bcl-2 but not by VAD. Bcl-2 consistently blocks SAHA-induced apoptosis. During SAHA treatment, Bcl-2 and Bcl-XL decrease, and Bid is proteolytically cleaved, whereas Bax and Bak expression remains constant. Bid cleavage, but not Bcl-2/Bcl-XL decrease, is completely suppressed by VAD. SAHA does not activate p53, and pifithrin-α (a pharmacological p53 inhibitor) does not attenuate SAHA-induced apoptosis, negating a role of p53 in SAHA-induced apoptosis. SAHA induces histone acetylation, which is not affected by VAD, Bcl-2, or pifithrin-α. Trichostatin A can also induce apoptosis and histone acetylation in renal tubular cells. Together, the results have shown evidence for renal toxicity of histone deacetylase inhibitors. The toxicity may be related to protein acetylation and decrease of antiapoptotic proteins including Bcl-2 and Bcl-XL. The American Society for Pharmacology and Experimental Therapeutics ER -