Metformin synergistically enhances antitumor activity of cisplatin in gallbladder cancer via the PI3K/AKT/ERK pathway

Abstract

Metformin (Met) is a widely used antidiabetic drug and has demonstrated interesting anticancer effects in various cancer models, alone or in combination with chemotherapeutic drugs. The aim of the present study is to investigate the synergistic effect of Met with cisplatin (Cis) on the tumor growth inhibition of gallbladder cancer cells (GBC-SD and SGC-996) and explore the underlying mechanism. Cells were treated with Met and/or Cis and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay and immunohistochemistry. The results demonstrated that Met and Cis inhibited the proliferation of gallbladder cancer cells, and combination treatment with Met and Cis resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with Met and Cis caused G0/G1 phase arrest by upregulating P21, P27 and downregulating CyclinD1, and induced apoptosis through decreasing the expression of p-PI3K, p-AKT, and p-ERK. In addition, pretreatment with a specific AKT activator (IGF-1) significantly neutralized the pro-apoptotic activity of Met + Cis, suggesting the key role of AKT in this process. More importantly, in nude mice model, Met and Cis in combination displayed more efficient inhibition of tumor weight and volume in the SGC-996 xenograft mouse model than Met or Cis alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which is consistent with our in vitro results. In conclusion, our findings indicate that the combination therapy with Met and Cis exerted synergistic antitumor effects in gallbladder cancer cells through PI3K/AKT/ERK pathway, and combination treatment with Met and Cis would be a promising therapeutic strategy for gallbladder cancer patients.

Matrine combined with cisplatin synergistically inhibited urothelial bladder cancer cells via down-regulating VEGF/PI3K/Akt signaling pathway

“…In our study, we found that matrine could also arrest the cell cycle of EJ and T24 cells at G1 phase, while cisplatin increased primarily the S phase cell percentage in comparison with the untreated cells, which was consistent with many other researchers’ findings [ 19 ]. However, Bi’s research found that in gallbladder cancer a proportion of cells at the G1 phase increased compared with that of the control when treated with cisplatin [ 20 ]. The effect of cisplatin on the cell cycle distribution is still controversial, and remains to be further explored.…”

Antitumour Effects of Astaxanthin and Adonixanthin on Glioblastoma

“…Moreover, these compounds increased the expression of p27, a cyclin-dependent kinase inhibitor ( Figure 4 E). In a previous report, the phosphorylation of ERK1/2 and Akt increased the expression of cyclinD1 and decreased the expression of p27 [ 31 , 32 , 33 ]. These results indicate that the antitumour effect of both astaxanthin and adonixanthin may be mediated by not cell death but cell cycle arrest.…”

Pristimerin enhances the effect of cisplatin by inhibiting the miR‑23a/Akt/GSK3β signaling pathway and suppressing autophagy in lung cancer cells

“…It has been reported that Pris is a potential anticancer drug that can induce apoptosis in pancreatic cancer cells and colorectal cancer cells (15,41). Bi et al (42) reported that metformin synergistically enhances Cis-induced apoptosis via increasing the inhibition of Akt activity mediated by cisplatin. Liao et al (43) also revealed that matrine enhances the pro-apoptotic ability of Cis in urothelial bladder cancer cells through increasing the inhibition of Akt activity mediated by Cis (43).…”