TY - JOUR
T1 - Induction of apoptosis in renal tubular cells by histone deacetylase inhibitors, a family of anticancer agents
AU - Dong, Guie
AU - Wang, Lysa
AU - Wang, Cong Yi
AU - Yang, Tianxin
AU - Kumar, M. Vijay
AU - Dong, Zheng
PY - 2008/6
Y1 - 2008/6
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.
AB - 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.
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U2 - 10.1124/jpet.108.137398
DO - 10.1124/jpet.108.137398
M3 - Article
C2 - 18310471
AN - SCOPUS:44249089268
SN - 0022-3565
VL - 325
SP - 978
EP - 984
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -