Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products

Abstract

Chemoresistance remains a major problem in the treatment of gastric cancer patients. Hence, novel pharmacological agents that can overcome drug resistance are urgently required. Whether simvastatin can sensitize the gastric cancer to the antitumor effects of capecitabine in vitro and in vivo was investigated. The effect of simvastatin on the proliferation of gastric cancer cells was examined by mitochondrial dyeuptake 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, apoptosis by esterase staining, NF-κB activation by DNA binding assay, and protein expression by western blot analysis. The effect of simvastatin on the tumor growth in xenograft mouse model of human gastric cancer was also examined. Simvastatin suppressed the proliferation of gastric cancer cells, enhanced the apoptotic effects of capecitabine, suppressed the constitutive activation of NF-κB, and abrogated the expression of cyclooxygenase-2 (COX-2), cyclin D1, Bcl-2, survivin, CXC motif receptor 4, and MMP-9 proteins. In a xenograft mouse model, we observed that the administration of simvastatin alone (5 mg/ kg body weight, intraperitoneal thrice/week) significantly suppressed the growth of the tumor and this effect was further potentiated by capecitabine treatment. As compared to the vehicle control, simvastatin also suppressed the expression of NF-κB-regulated gene products such as cyclin D1, COX-2, ICAM-1, MMP-9, survivin, Bcl-xL, and XIAP in tumor tissues. Overall, our results demonstrate that simvastatin can enhance the effects of capecitabine through suppression of NF-κB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.

The effect of statins on cancer cells—review

“…Apart from the studies mentioned above [38] that revealed that simvastatin treatment can decrease the tumor size in mice that had engrafted prostate cancer cells, many more such examples exist. Favorable effect of statins in vitro that were subsequently confirmed by studies in mice xenografts have also been demonstrated in the case of gastric [62], renal [63], and breast cancer [37,54], as well as for glioblastoma [64]. For example, it was shown that simvastatin inhibited the growth of the tumors derived from MDA MB 231 human breast cancer cell xenografts in mice [54].…”

“…A study was carried out to investigate the use of simvastatin in a combination therapy with capecitabine in gastric cancer treatment [62]. It transcribed that simvastatin inhibited proliferation and enhanced apoptotic effect on cancer cells in vitro.…”

Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel

“…A549 cells were injected subcutaneously into the mice as described previously [55]. In brief, A549 cells were harvested from subconfluent cultures, washed once in serum-free medium, and resuspended in PBS.…”

NF‐κB Signaling in Gastric Cancer

“…A number of NF-κB-regulated gene products, including cyclin D1, COX-2, etc. have been closely linked with the development of chemoresistance in gastric cancer [151]. Thus, a control of NF-κB activity might be a useful therapeutic strategy to augment conventional therapy and circumvent chemoresistance in gastric cancer patients.…”