Forskolin sensitizes pancreatic cancer cells to gemcitabine via Stat3 and Erk1/2 inhibition

Abstract

Cytotoxic chemotherapy, including gemcitabine-based regimens, represents the mainstay of treatment for locally advanced and metastatic pancreatic cancer. However, the response to chemotherapy is absolutely unsatisfactory and the prognosis of pancreatic cancer remains very poor. Therefore, it would be greatly beneficial to develop therapeutic approaches that cause pancreatic cancer cells to increase their sensitivity to chemotherapeutic drug gemcitabine. Forskolin is a natural cAMP elevating agent used for centuries in traditional medicine and its safety has been also documented in modern medicine. Notably, forskolin is emerging as a very interesting molecule to possibly use in cancer therapy. In the present study, we investigated the effects of forskolin on the proliferation, migration and sensitivity to gemcitabine of pancreatic cancer cells, carrying out flow cytometry-based assays of cell-cycle progression and cell death, wound-healing and MTT assays, direct cell number counting and immunoblotting experiments. Here, we show that forskolin exerts significant growth and migratory inhibitory effects on Panc-1 and AsPC-1 pancreatic cancer cells. In addition, we report that forskolin strongly enhances gemcitabine-induced antiproliferative effects by both cell cycle inhibition and cell death induction. Importantly, the forskolin-induced potentiation of antiproliferative effect by gemcitabine is preceded and accompanied by a strong inhibition of phosphorylation levels of Stat3 and Erk1/2 proteins. Altogether, our data enforce the evidence of forskolin acting as a compound with anticancer activity and provide a rationale for the design of in vivo/clinical studies exploring forskolin as a gemcitabine sensitizer/adjuvant to possibly use in pancreatic cancer patients.

Keywords

• forskolin
• gemcitabine
• Erk1/2
• Stat3
• pancreatic cancer
• combination therapy