Chen Zixuan, Jia Xing, Cai Yuesong, Song Ya, Tong Yanjun, Cheng Sheng, Liu Min
Department of Urology, Tongren Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, 200336, China.
College of Medicine, Yanbian University, Yanji, 133002, China.
Heliyon. 2024 Jul 18;10(14):e34834. doi: 10.1016/j.heliyon.2024.e34834. eCollection 2024 Jul 30.
Clear Cell Renal Cell Carcinoma (ccRCC), the most prevalent form of renal cell carcinoma (RCC), poses a significant threat to human health due to its rising morbidity and mortality rates. Sunitinib, a pivotal targeted drug for the treatment of ccRCC, presents a significant challenge due to the high susceptibility of ccRCC to resistance. HSP90 inhibitor AUY922 has demonstrated anti-tumor activity in a range of cancer types. However, its efficacy in combination with sunitinib for ccRCC treatment has not been evaluated. In this study, we employed bioinformatics, network pharmacology, and in vitro assays to verify that AUY922 inhibits cell viability, proliferation, and migration of ccRCC cell lines 786-O and ACHN, with IC50s of 91.86 μM for 786-O and 115.5 μM for ACHN. The effect of AUY922 enhancing the inhibitory effect of sunitinib on ccRCC was further confirmed. The CCK-8 assay demonstrated that the IC50 of sunitinib was reduced from 15.10 μM to 11.91 μM for 786-O and from 17.65 μM to 13.66 μM for ACHN, after the combined application of AUY922. The EdU assay and wound healing assay indicated that AUY922 augmented the inhibitory impact of sunitinib on the proliferation and migration of ccRCC cells. Western blot and RT-PCR analyses demonstrated that AUY922 increased the sensitivity of ccRCC cells to sunitinib by targeting the HIF-1α/VEGFA/VEGFR pathway. Our study represents the first investigation into the role and mechanism of AUY922 in enhancing the sensitivity of ccRCC to sunitinib. In conclusion, the findings indicate the potential for AUY922 to enhance the therapeutic efficacy of sunitinib and overcome sunitinib resistance in ccRCC.
透明细胞肾细胞癌（ccRCC）是肾细胞癌（RCC）最常见的形式，由于其发病率和死亡率不断上升，对人类健康构成重大威胁。舒尼替尼是治疗ccRCC的关键靶向药物，由于ccRCC对耐药性高度敏感，因此面临重大挑战。HSP90抑制剂AUY922在一系列癌症类型中已显示出抗肿瘤活性。然而，其与舒尼替尼联合用于ccRCC治疗的疗效尚未得到评估。在本研究中，我们采用生物信息学、网络药理学和体外试验来验证AUY922可抑制ccRCC细胞系786 - O和ACHN的细胞活力、增殖和迁移，786 - O的IC50为91.86 μM，ACHN的IC50为115.5 μM。进一步证实了AUY922增强舒尼替尼对ccRCC抑制作用的效果。CCK - 8试验表明，联合应用AUY922后，786 - O的舒尼替尼IC50从15.10 μM降至11.91 μM，ACHN的从17.65 μM降至13.66 μM。EdU试验和伤口愈合试验表明，AUY922增强了舒尼替尼对ccRCC细胞增殖和迁移的抑制作用。蛋白质免疫印迹法和逆转录 - 聚合酶链反应分析表明，AUY922通过靶向HIF - 1α/VEGFA/VEGFR途径增加了ccRCC细胞对舒尼替尼的敏感性。我们的研究首次探讨了AUY922在增强ccRCC对舒尼替尼敏感性方面的作用和机制。总之，研究结果表明AUY922具有增强舒尼替尼治疗效果并克服ccRCC中舒尼替尼耐药性的潜力。
