Nursing assistance for psychological adjustment of gastrointestinal cancer patients undergoing laparotomy in the perioperative period

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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

Additional file 1 of Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy

Additional file 1: Fig. S1. IC50 values of L-OHP, simvastatin, or fluvastatin in colorectal cancer cell lines. Cell survival was detected by WST-8 assy. IC50 values were computed by using the survival rate data to a logistic curve. Fig. S2. Combination index values of L-OHP and simvastatin or fluvastatin in LoVo and Colon26 cells. Cell survival was detected by WST-8 assy. IC50 values were computed by using the survival rate data to a logistic curve. Fig. S3. Safety of combined treatment with L-OHP and simvastatin in mice. Male Balb/c mice (n=9 per group) were randomized and received three intravenous injections of L-OHP (6 or 10 mg/kg) or vehicle (5% glucose solution) on days 0, 7, and 14; on day 0, simvastatin was administered 12 h after L-OHP administration. Simvastatin was treated orally (p.o.) at a 10 or b 50 mg/kg once a day for 3 weeks. Mice were weighed before the first treatment and every day during the treatment period. Mean values and S.E.M. are shown. Fig. S4. Simvastatin suppressed LOHP-induced mechanical sensitivity in mice. Male Balb/c mice (n=9 per group) were randomized and received three intravenous injections of L-OHP (6 or 10 mg/kg) or vehicle (5% glucose solution) over 3 weeks (Days 0, 7, and 14). On day 0, simvastatin was administered 12 h after L-OHP administration. Simvastatin was treated orally (p.o.) at a 10 or b 50 mg/kg once a day for 3 weeks. Mechanical allodynia was analyzed using the 0.4 g von Frey filaments (Ugo Basile). Pain scores obtained from both hind paws of each mouse for five stimuli were averaged and recorded. Mean values and S.E.M. are shown. Statistical analysis was performed by ANOVA with Dunnett’s, and the difference was considered significant when P < 0.05. Fig. S5. Simvastatin suppressed LOHP-induced mechanical sensitivity in mice. Male Balb/c mice (n=9 per group) were randomized and received three intravenous injections of L-OHP (6 or 10 mg/kg) or vehicle (5% glucose solution) over 3 weeks (Days 0, 7, and 14). On day 0, simvastatin was administered 12 h after L-OHP administration. Simvastatin was treated orally (p.o.) at a 10 or b 50 mg/kg once a day for 3 weeks. Mechanical allodynia was analyzed using the 1.4 g von Frey filaments (Ugo Basile). Pain scores obtained from both hind paws of each mouse for five stimuli were averaged and recorded. Mean values and S.E.M. are shown. Statistical analysis was performed by ANOVA with Dunnett’s, and the difference was considered significant when P < 0.05. Fig. S6. Simvastatin suppressed LOHP-induced ERK1/2 phosphorylation in the lumber spinal cord of mice. Male Balb/c mice (n=5 per group) were randomized and received three intravenous injections of L-OHP (6 or 10 mg/kg) or vehicle (5% glucose solution) over 3 weeks (Days 0, 7, and 14). On day 0, simvastatin was administered 12 h after L-OHP administration. Simvastatin was treated orally (p.o.) at 10 or 50 mg/kg once a day for 3 weeks. After 3 weeks, the lumbar spinal cords of mice were quickly dissected and homogenized, and analyzed by western blot using the anti-phospho-ERK1/2 and anti-ERK1/2 antibodies. The amount of detected proteins were measured based on densitometry. The results are exemplary five independent experiments. Mean values and S.D. are shown. Statistical analysis was performed by ANOVA with Dunnett’s, and the difference was considered significant when P < 0.05

Additional file 2 of Statins enhances antitumor effect of oxaliplatin in KRAS-mutated colorectal cancer cells and inhibits oxaliplatin-induced neuropathy

Additional File 2: Supplementary materials and methods