Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy

Abstract

Background KRAS mutations are fraught with the progression of colorectal cancer and resistance to chemotherapy. There are pathways such as extracellular regulated protein kinase 1/2 (ERK1/2) and Akt downstream and farnesylation and geranylgeranylation upstream that are activated upon mutated KRAS. Previous studies have shown that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are effective to treat KRAS mutated colorectal cancer cells. Increased doses of oxaliplatin (L-OHP), a well-known alkylating chemotherapeutic drug, causes side effects such as peripheral neuropathy due to ERK1/2 activation in spinal cords. Hence, we examined the combinatorial therapeutic efficacy of statins and L-OHP to reduce colorectal cancer cell growth and abrogate neuropathy in mice. Methods Cell survival and confirmed apoptosis was assessed using WST-8 assay and Annexin V detection kit. Detection of phosphorylated and total proteins was analyzed the western blotting. Combined effect of simvastatin and L-OHP was examined the allograft mouse model and L-OHP-induced neuropathy was assessed using cold plate and von Frey filament test. Results In this study, we examined the effect of combining statins with L-OHP on induction of cell death in colorectal cancer cell lines and improvement of L-OHP-induced neuropathy in vivo. We demonstrated that combined administration with statins and L-OHP significantly induced apoptosis and elevated the sensitivity of KRAS-mutated colorectal cancer cells to L-OHP. In addition, simvastatin suppressed KRAS prenylation, thereby enhancing antitumor effect of L-OHP through downregulation of survivin, XIAP, Bcl-xL, and Bcl-2, and upregulation of p53 and PUMA via inhibition of nuclear factor of κB (NF-κB) and Akt activation, and induction of c-Jun N-terminal kinase (JNK) activation in KRAS-mutated colorectal cancer cells. Moreover, simvastatin enhanced the antitumor effects of L-OHP and suppressed L-OHP-induced neuropathy via ERK1/2 activation in vivo. Conclusion Therefore, statins may be therapeutically useful as adjuvants to L-OHP in KRAS-mutated colorectal cancer and may also be useful in the treatment of L-OHP-induced neuropathy.

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 ).…”

Licochalcone H Targets EGFR and AKT to Suppress the Growth of Oxaliplatin -Sensitive and -Resistant Colorectal Cancer Cells

“…Its major risk factors are obesity, diabetes, smoking, and inflammatory bowel disease ( Gausman et al ., 2020 ). Chemotherapy is a general strategy for the treatment of CRC before and after surgery; 5-fluorouracil, oxaliplatin (Ox), and irinotecan are mainly used alone or in combination as FOLFOX, FOLFIRI, or FOLFRINOX ( Tsubaki et al ., 2023 ). Ox was the first platinum-based chemotherapeutic agent that improves the moderate response to 5-fluorouracil and limits cisplatin-mediated side effects ( Graham et al ., 2004 ).…”