Synergistic antitumor activity of regorafenib and rosuvastatin in colorectal cancer

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.

Pharmacokinetic interaction between regorafenib and atorvastatin in rats

“…These reports underline the importance of evaluating interactions between ATO and REG. Yuan et al [38] found that the combination of rosuvastatin and REG had a synergistic effect, which may be a new standard of colorectal cancer treatment.…”

The role of gut microbiota and drug interactions in the development of colorectal cancer

“…Statins may be considered as targeted therapy for CRC ( Shailes et al, 2022 ). Meanwhile, in the treatment, statins can enhance the anticancer activity of the chemotherapeutic drug oxaliplatin, enhance the sensitivity of radiotherapy for CRC and synergize the antitumor effect of the targeted drug regorafenib, which may arise from the weakening of stemness and drug resistance of CRC cells by statins ( Karagkounis et al, 2018 ; Gao et al, 2021 ; Gonçalves et al, 2021 ; Tsubaki et al, 2023 ; Yuan et al, 2023 ). Pravastatin, a metabolite of intestinal flora, can promote interleukin (IL)-13 release from type Ⅱ innate lymphocytes through IL-33 signaling, which has been shown to promote self-renewal of pluripotent intestinal stem cells at the base of intestinal crypts ( Zhu et al, 2019 ; Deng et al, 2021 ).…”