Wang Ligang, Wang Ying, Xie Qiqi, Xu Songcheng, Yang Chen, Liu Fei, Liu Yang, Wang Fuwei, Chen Weinan, Li Jianchun, Sun Litao
Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Health Management Center, Health Promotion Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
Int J Pharm X. 2024 Aug 26;8:100280. doi: 10.1016/j.ijpx.2024.100280. eCollection 2024 Dec.
RCC is a malignant tumor arising from the urothelium of renal parenchyma that remains challenging to be treated. In this study, we assessed the anti-tumor effects of Resveratrol liposomes (RES-lips) combined with sorafenib on renal cell carcinoma (RCC) and explored the potential mechanisms underlying the improvement of sorafenib resistance models. Tumor growth and survival following treatment with sorafenib alone or in combination with RES-lips was evaluated in a RCC xenograft mouse model. Flow cytometry results demonstrated that the combination of RES-lips and sorafenib significantly enhanced the G1/S phase arrest of sorafenib-resistant cells. When compared with the PBS or monotherapy groups, treatment with RES-lips combined with sorafenib exhibited significant inhibition of tumor growth in the RCC xenograft mouse model with tumor growth inhibition (TGI) rates and complete remission (CR) rates of 90.1 % and 50 %, respectively. Concersely, the maximum TGI rate was 53.6 % in the RES-lips monoherapy group and 29.2 % and in the sorafenib monotherapy group, and no animals achieved CR. Additionally, the current combination therapy promoted the proliferation of unactivated splenic lymphocytes and the proliferation of soybean protein A- and lipopolysaccharide-stimulated lymphocytes compared with PBS or monotherapy treatments. Further western blotting analysis suggested that RES-lips may enhance the resistance of RCC to sorafenib by inhibiting PI3K-AKT-mTOR and VHL-HIF signaling pathways, ultimately augmenting the tumor growth inhibition effect of the combination therapy. RES-lips may improve the sorafenib resistance in RCC, and the underlying mechanism may be related to the regulation of PI3K-AKT-mTOR and VHL-HIF signaling pathways.
肾细胞癌（RCC）是一种起源于肾实质尿路上皮的恶性肿瘤，其治疗仍然具有挑战性。在本研究中，我们评估了白藜芦醇脂质体（RES-lips）联合索拉非尼对肾细胞癌（RCC）的抗肿瘤作用，并探讨了改善索拉非尼耐药模型的潜在机制。在RCC异种移植小鼠模型中评估了单独使用索拉非尼或与RES-lips联合使用后的肿瘤生长和生存期。流式细胞术结果表明，RES-lips与索拉非尼联合使用可显著增强索拉非尼耐药细胞的G1/S期阻滞。与PBS或单药治疗组相比，RES-lips联合索拉非尼治疗在RCC异种移植小鼠模型中显示出对肿瘤生长的显著抑制，肿瘤生长抑制（TGI）率和完全缓解（CR）率分别为90.1%和50%。相反，RES-lips单药治疗组的最大TGI率为53.6%，索拉非尼单药治疗组为29.2%，且没有动物达到CR。此外，与PBS或单药治疗相比，目前的联合治疗促进了未激活脾淋巴细胞的增殖以及大豆蛋白A和脂多糖刺激的淋巴细胞的增殖。进一步的蛋白质印迹分析表明，RES-lips可能通过抑制PI3K-AKT-mTOR和VHL-HIF信号通路来增强RCC对索拉非尼的耐药性，最终增强联合治疗的肿瘤生长抑制作用。RES-lips可能改善RCC对索拉非尼的耐药性，其潜在机制可能与PI3K-AKT-mTOR和VHL-HIF信号通路的调节有关。
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