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Retinoic Acid and the Histone Deacetylase Inhibitor Trichostatin A Inhibit the Proliferation of Human Renal Cell Carcinoma in a Xenograft Tumor Model

Authors' Affiliations: ¹ Departments of Pharmacology, ² Pathology, and ³ Urology, and ⁴ Division of Hematology/Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York; ⁵ Mount Kisco Medical Group, Mount Kisco, New York; ⁶ Pharmaceutical Research Institute, Bristol-Myers Squibb, New Brunswick, New Jersey; and ⁷ Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Lorraine J. Gudas, 1300 York Avenue, Room E-409, New York, NY 10021. Phone: 212-746-6250; Fax: 212-746-8858; E-mail: ljgudas{at}med.cornell.edu.

Purpose: Therapy for advanced renal cell carcinoma (RCC) is ineffective in the majority of patients. We have previously reported that retinoid-induced up-regulation of retinoic acid receptor ß (RARß) correlated with antitumor effects in RCCs. Recent studies show that there is a reduction in the level of RARß₂ expression in cancer cells due in part to histone hypoacetylation. Therefore, we tested whether combining histone deacetylase inhibitors with retinoic acid (RA) would restore RARß₂ receptor expression, leading to increased growth inhibition in RCC cells.

Experimental Design: Cell proliferation, Western blot, and reverse transcription-PCR analyses of two RA-resistant RCC cell lines, SK-RC-39 and SK-RC-45, were assessed in the presence of all-trans retinoic acid (ATRA), trichostatin A (TSA), or the combination of ATRA and TSA. Analysis of apoptosis was also done on SK-RC-39 cells treated with these combinations. Additionally, a xenograft tumor model (SK-RC-39) was used in this study to investigate the efficacy of a liposome-encapsulated, i.v. form of ATRA (ATRA-IV) plus TSA combination therapy.

Results: Enhanced inhibition of the proliferation of RCC cell lines and of tumor growth in a xenograft model was observed with the combination of ATRA plus TSA. Reactivation of RARß₂ mRNA expression was observed in SK-RC-39 and SK-RC-45 cells treated with TSA alone or TSA in combination with ATRA. A partial G₀-G₁ arrest and increased apoptosis were observed with SK-RC-39 cells on treatment with ATRA and TSA.

Conclusions: The combination of ATRA and the histone deacetylase inhibitor TSA elicits an additive inhibition of cell proliferation in RCC cell lines. These results indicate that ATRA and histone deacetylase inhibitor therapies should be explored for the treatment of advanced RCC.

Key Words: histone acetylation • kidney cancer • retinoic acid receptors • retinol • SK-RC-39 • SK-RC-45 • vitamin A

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