Journal
CLINICAL CANCER RESEARCH
Volume 11, Issue 9, Pages 3558-3566Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-04-1155
Keywords
-
Categories
Funding
- NCI NIH HHS [R01 CA92542, T32 CA062948] Funding Source: Medline
- NIDCR NIH HHS [R01 DE10389] Funding Source: Medline
Ask authors/readers for more resources
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 p (RARp) correlated with antitumor effects in RCCs. Recent studies show that there is a reduction in the level of RAR beta(2) expression in cancer cells due in part to histone hypoacetylation. Therefore, we tested whether combining histone deacetylase inhibitors with retinoic acid (RA) would restore RAR beta(2) 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 RAR beta(2) 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 GO-G, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available