Abstract
Abstract Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor (TKI). It is more effective for renal cell carcinoma (RCC) treatment than conventional immunotherapy, but it causes the resistance and severe side effects in some cases. As a combination therapy might be one solution for them, we paid attention to sodium butyrate (NaBu). It is classified into histone deacetylase (HDAC) inhibitor and it is reported HDAC inhibitors can enhance anti-cancer effect of existent drugs including TKI. So, we examined combination effect of SU and NaBu. And to reveal the target of this combination, we examined effects of SU and NaBu on connexin (Cx), which is a component of gap junction (GJ) and tumor suppressors. We assessed effect of SU and NaBu combination on ACHN (human RCC cell line) cell proliferation by MTT assay and this combination exhibited a synergistic anti-proliferative effect. By real-time PCR, we detected up-regulation of Cx32 mRNA by NaBu. Moreover, NaBu depicted the up-regulated Cx32 protein expression, which was observed by confocal fluorescence microscope. Hemi-channel (Cx hexamer) function was assessed by propidium iodide (PI) uptake into cells. We found both SU and NaBu enhanced PI uptake significantly. GJ function was assessed by scrape-loading. It was confirmed GJ didn't function in ACHN cells and neither SU nor NaBu affected its function. So, it was suggested NaBu could up-regulate Cx32 expression and both SU and NaBu could enhance hemi-channel function. However, we couldn't reveal whether GJ was related to enhancing SU sensitivity. So, we used GJ positive or negative H28 (human malignant mesothelioma cell line) to reveal this matter. As a result, GJ positive cells were more sensitive to SU than negative ones. On the other hand, inhibition of GJ function didn't restore viability of GJ positive cells. In conclusion, we demonstrated the combination therapy of SU and NaBu had synergistic anti-proliferative effect, so it could be a prominent therapy for RCC. Furthermore, we found Cx could be involved in this combination effect, which might be performed in GJ-independent manner. Citation Format: Miaki Uzu, Hiromi Sato, Rina Suzuki, Hiroko Okuzawa, Sana Siddig, Guligena Tuerdi, Sayumi Suzuki, Yuki Nomura, Yuko Sekine, Tomohiro Yano, Koichi Ueno. Connexin might be involved in anti-cancer combination effect of sunitinib and sodium butyrate. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1043. doi:10.1158/1538-7445.AM2013-1043
Published Version
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