Metformin inhibited esophageal squamous cell carcinoma proliferation in vitro and in vivo and enhanced the anti-cancer effect of cisplatin

Abstract

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor prognosis in China. Chemotherapy now is one of the most frequently used treatments for patients with ESCC in middle or late stage, however the effects were often limited by increased chemoresistance or treatment toxicity. So it is urgent to find new drugs to treat ESCC patients. Metformin with low cost and toxicity has proved to have anti-cancer effects in numerous cancers, while its role and mechanism in ESCC has seldom been studied. In the present study, we found that metformin exhibited not only an anti-proliferation ability in a dose and time dependent manner but also a proapoptosis effect in a dose dependent manner in ESCC cell line KYSE450. Our in vivo experiment also showed that metformin markedly inhibited KYSE450 xenograft tumors growth compared to those treated with normal saline. What’s more, no obvious toxic reactions were observed. To further explore the underlying mechanism, we found that metformin treatment could significantly damp the expression of 4EBP1 and S6K1 in KYSE 450 cells in vitro and in vivo, furthermore, the p-4EBP1 and p-S6K1 expression in KYSE 450 cells were also inhibited greatly in vitro and in vivo. During the therapy of cancer, in order to overcome side effects, combination therapy was often used. In this paper, we demonstrated that metformin potentiated the effects of cisplatin via inhibiting cell proliferation and promoting cell apoptosis. Taken together, metformin owned the potential anti-cancer effect on ESCC in monotherapy or was combined with cisplatin and these results laid solid basis for the use of metformin in ESCC.

Role of p53 Family Proteins in Metformin Anti-Cancer Activities

“…Furthermore, metformin can inhibit migration and invasion of ESCC cells via inhibiting NF-κB nuclear localization67 or AKT signaling68 (Figure 1B). Moreover, metformin can enhance esophagus cancer cell sensitivity to chemotherapeutic drugs, 5-FU69 or cisplatin70, 71. Currently, there is one clinical trial approved by the FDA that is exploring the effect of metformin on ESCC (Table 1).…”

Metformin Inhibits Esophageal Squamous Cell Carcinoma Viability and Mobility in vitro through Down-regulation of Long Non-coding RNA CCAT1 and SPRY4-IT1

“…In the past decades, metformin has been confirmed to be valuable in esophageal cancer patients [6][7][8]. For instance, it demonstrated the efficient anti-viability effect of metformin on ESCC cells [14,17,18]. Also, this work demonstrated that metformin inhibited the viability and migration of ESCC cells in a dose-and time-dependent manner (Figure 1).…”

“…Research shows that administration of metformin improves the overall survival (OS) and distant metastatic-free survival (DFS) rates in patients with ECA [7]. Pre-clinical studies indicated that metformin sensitizes chemotherapy [13][14][15] or radiotherapy [16]. Additionally, it induces apoptosis and autophagy [17], inhibits proliferation [18,19], as well as triggers cell cycle arrest in esophageal cancer [18].…”

Nephroprotection and chemotherapy sensitivity impact of metformin during cisplatin therapy; an updated review

“…In fact, it supports the mitochondrial biosynthetic metabolism from the additional carbon source (22). A study on esophageal squamous cell carcinoma as the most common type of cancer in China, also showed that metformin has an anti-proliferation ability and reduces xenograft tumor proliferation considerably by decreasing protein expression such as ribosomal protein S6 kinase beta-1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) (23). The anti-apoptotic effect of surviving and AKT is related to chemotherapy resistance in some types of cancers.…”