Sato Hiromi, Uzu Miaki, Kashiba Tatsuro, Suzuki Rina, Fujiwara Takuya, Okuzawa Hiroko, Ueno Koichi
Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba 260-8675, Japan.
Center of Preventive Medical Science, Chiba University, Chuo-ku, Chiba 260-8675, Japan.
Oncol Lett. 2017 Jul;14(1):937-943. doi: 10.3892/ol.2017.6217. Epub 2017 May 19.
Sunitinib (SU) is a small molecule that inhibits the receptor tyrosine kinase (RTK) signaling pathway, and has been clinically used to treat advanced renal cell carcinoma (RCC). However, SU is not always effective as RCC is a highly chemoresistant type of cancer. One of the factors that confer chemoresistance to RCC is a hypoxic condition. Lack of oxygen activates hypoxia-inducible factor (HIF) protein, which is followed by the upregulation of growth factors, including vascular endothelial growth factor and activation of the RTK signaling pathway. In this context, histone deacetylase inhibitors (HDACIs) are considered prominent combined agents for SU as they downregulate the expression of HIFs. Therefore, the present study aimed to investigate the effectiveness of combined treatment with SU and sodium butyrate (NaBu), an HDACI. Long-term exposure to these agents exerted a stronger growth inhibitory effect in RCC cell lines compared with single treatment groups. Furthermore, combined treatment suppressed HIF-2α protein, which was induced under hypoxic conditions. In addition, this combination sustained the activity of the RTK signaling pathway to the level of intact cells, although a single treatment with SU or NaBu was demonstrated to increase this activity. Overall, it is suggested that the combination of SU and NaBu is effective for overcoming drug resistance in RCC.
舒尼替尼（SU）是一种抑制受体酪氨酸激酶（RTK）信号通路的小分子，已在临床上用于治疗晚期肾细胞癌（RCC）。然而，由于RCC是一种高度化疗耐药的癌症类型，SU并不总是有效。赋予RCC化疗耐药性的因素之一是缺氧状态。缺氧会激活缺氧诱导因子（HIF）蛋白，随后包括血管内皮生长因子在内的生长因子上调，RTK信号通路被激活。在这种情况下，组蛋白去乙酰化酶抑制剂（HDACIs）被认为是SU的重要联合用药，因为它们可下调HIFs的表达。因此，本研究旨在探讨SU与HDACI丁酸钠（NaBu）联合治疗的有效性。与单一治疗组相比，长期暴露于这些药物对RCC细胞系具有更强的生长抑制作用。此外，联合治疗可抑制缺氧条件下诱导产生的HIF-2α蛋白。此外，尽管单独使用SU或NaBu可增加RTK信号通路的活性，但这种联合用药可将RTK信号通路的活性维持在完整细胞的水平。总体而言，提示SU与NaBu联合用药对克服RCC的耐药性有效。
