Buformin is an old anti-diabetic agent and manifests potent anti-
tumor activities in several
malignancies. In the present study, we aimed to explore the functions of
buformin in human
cervical cancer. As our data shown,
buformin exhibited significant anti-proliferative effects in a dose-dependent manner in 4
cervical cancer cell lines. Compared to the control,
buformin notably suppressed colony formation and increased ROS production in C33A, Hcc94 and SiHa cells. Flow cytometric analysis showed that
buformin induced marked cell cycle arrest but only resulted in mild apoptosis. The invasion of C33A and SiHa cells sharply declined with
buformin treatment. Consistently, western blotting showed that
buformin activated AMPK and suppressed S6,
cyclin D1, CDK4, and MMP9. Moreover, we found that
buformin enhanced
glucose uptake and LDH activity, increased
lactate level, while decreased
ATP production in
cervical cancer cells. In addition, low doses of
buformin synergized with routine chemotherapeutic drugs (such as
paclitaxel, cisplatin, and 5-FU) to achieve more significant anti-
tumor effects. In vivo, a single use of
buformin exerted moderate anti-
tumor effects, and the combination with
buformin and
paclitaxel exhibited even greater suppressive effects.
Buformin also consistently showed synergistic effects with
paclitaxel in treating primary cultures of
cervical cancer cells. Take together, we are the first to demonstrate that
buformin suppresses cellular proliferation and invasion through the AMPK/S6 signaling pathway, which arrests cell cycle and inhibits cellular invasion.
Buformin also could synergize with routine
chemotherapies, producing much more powerful anti-
tumor effects. With these findings, we strongly support
buformin as a potent choice for treating
cervical cancer, especially in combination with routine
chemotherapy.