Synergistic anti-tumour activity of sorafenib in combination with pegylated resveratrol is mediated by Akt/mTOR/p70S6k-4EBP-1 and c-Raf7MEK/ERK signaling pathways

Ligang Wang; Hao Wu; Ying Wang; Songcheng Xu; Chen Yang; Tingting Zhang; Yang Liu; Fuwei Wang; Weinan Chen; Jianchun Li; Litao Sun

doi:10.1016/j.heliyon.2023.e19154

Synergistic anti-tumour activity of sorafenib in combination with pegylated resveratrol is mediated by Akt/mTOR/p70S6k-4EBP-1 and c-Raf7MEK/ERK signaling pathways

Heliyon. 2023 Aug 19;9(8):e19154. doi: 10.1016/j.heliyon.2023.e19154. eCollection 2023 Aug.

Authors

Ligang Wang¹, Hao Wu², Ying Wang³, Songcheng Xu¹, Chen Yang¹, Tingting Zhang⁴, Yang Liu¹, Fuwei Wang⁵, Weinan Chen¹, Jianchun Li¹, Litao Sun¹

Affiliations

¹ Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310000, Zhejiang Province, PR China.
² Department of Ultrasound Medicine, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, Zhejiang Province, PR China.
³ Health Management Center, Health Promotion Center, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310000, Zhejiang Province, PR China.
⁴ Bengbu Medical College, Bengbu 230030, Anhui Province, PR China.
⁵ Department of Oncology and Cancer Biotherapy Center, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang, PR China.

Abstract

Introduction: To investigate the inhibitory effect of sorafenib combined with PEGylated resveratrol on renal cell carcinoma (RCC) and its potential mechanism.

Methods: MTT assay was used to detect the inhibitory effects of PEGylated resveratrol and sorafenib alone or combination on proliferation of RCC cells. Scratch and transwell assays were performed to examine the effects on the in vitro migration and invasion of RCC cells, respectively. The anti-tumor activity as well as splenic lymphocyte proliferation of the combination therapy was evaluated in the RCC xenograft mouse model. Western blotting method was used to detect changes in proteins involved in the antitumor efficacy related signaling pathways.

Results: Inhibitory effects of PEGylated resveratrol combined with sorafenib incubation on the proliferation of Renca cells was synergistically enhanced compared with the mono-incubation group (both P < 0.01, CI < 1). Scratch and transwell assays revealed that combined incubation could significantly inhibit the migration and invasion of 786-O cells in vitro. Combined PEGylated resveratrol with sorafenib could significantly inhibit the growth of Renca renal carcinoma in mice with the tumor growth inhibition (TGI) of 85.5% and one achieved complete remission on D14, while the two monotherapies were both below 43% on D14, suggesting that current combination may have synergistic anti-renal carcinoma activity. Compared with the control group, PEGylated resveratrol combined with sorafenib in vivo promoted the proliferation of unactivated splenic lymphocytes and the proliferation of lymphocytes stimulated with concanavalin A and lipopolysaccharide. Western blotting results showed that combination therapy may suppress the growth of renal cell carcinoma by inhibiting AKT/mTOR/p70S6k-4EBP-1 and c-Raf7MEK/ERK signaling pathways.

Conclusion: PEGylated resveratrol combined with sorafenib can achieve synergistic anti-RCC activity, and the mechanism may be related to the inhibition of Akt/mTOR/p70S6k-4EBP-1 and c-Raf7MEK/ERK signaling pathways.

Keywords: Akt/mTOR/p70S6k-4EBP-1; Combination; Kidney cancer; Resveratrol; Signaling pathway; Sorafenib; c-Raf7MEK/ERK.