Synergistic antitumor activity of regorafenib and rosuvastatin in colorectal cancer

Tao Yuan; Ruilin Wu; Weihua Wang; Yue Liu; Wencheng Kong; Bo Yang; Qiaojun He; Hong Zhu

doi:10.3389/fphar.2023.1136114

Synergistic antitumor activity of regorafenib and rosuvastatin in colorectal cancer

Front Pharmacol. 2023 Apr 17:14:1136114. doi: 10.3389/fphar.2023.1136114. eCollection 2023.

Authors

Tao Yuan¹, Ruilin Wu¹, Weihua Wang¹, Yue Liu¹, Wencheng Kong², Bo Yang¹, Qiaojun He^{1

3

4}, Hong Zhu^{1

4

5}

Affiliations

¹ Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
² Department of Gastroenterological Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China.
⁴ Cancer Center of Zhejiang University, Hangzhou, China.
⁵ Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Introduction: Colorectal cancer is one of the most prevalent life-threatening malignant tumors with high incidence and mortality. However, the efficacy of current therapeutic regimens is very limited. Regorafenib has been approved for second- or third-line treatment of patients who are refractory to standard chemotherapy diagnosed with metastatic colorectal cancer, but its clinical efficacy needs to be further improved. Accumulating evidence demonstrates that statins also possess potent anticancer activities. However, whether regorafenib and statins pose synergistic anticancer effects in colorectal cancer is still unclear. Methods: Sulforhodamine B (SRB) assays were applied to evaluate the anti-proliferative activity of regorafenib or/and rosuvastatin in vitro, and immunoblotting analysis were applied to detect the effects of regorafenib/rosuvastatin combined treatment on mitogen-activated protein kinase (MAPK) signaling and apoptosis-related proteins. MC38 tumors were applied to investigate the synergistic anticancer effects of regorafenib in combination with rosuvastatin in vivo. Results: We found that regorafenib in combination with rosuvastatin exerted significant synergistic inhibition against colorectal cancer growth in vitro and in vivo. Mechanistically, regorafenib and rosuvastatin combination synergistically suppressed MAPK signaling, a crucial signaling pathway promoting cell survival, as indicated by the reduction of phosphorylated MEK/ERK. In addition, regorafenib in combination with rosuvastatin synergistically induced the apoptosis of colorectal cancer in vitro and in vivo. Discussion: Our study demonstrated the synergistic anti-proliferative and pro-apoptotic effects of regorafenib/rosuvastatin combined treatment in colorectal cancer in vitro/vivo and might potentially be evaluated as a novel combination regimen for clinical treatment of colorectal cancer.

Keywords: MAPK signaling; colorectal cancer; regorafenib; rosuvastatin; statins.

Grants and funding

This work was supported by the State Key Program of the Natural Science Foundation of China (81830107), the Natural Science Foundation of China (82173836), Zhejiang Provincial Natural Science Foundation (LR19H310002 and LQ23H310009).