Combined treatment with tamoxifen and a fusicoccin derivative (ISIR-042) to overcome resistance to therapy and to enhance the antitumor activity of 5-fluorouracil and gemcitabine in pancreatic cancer cells

Abstract

Although progress has been made in chemothera-peutic strategies against pancreatic cancer, overall survival has not significantly improved over the past decade. Thus, the development of better therapeutic regimens remains a high priority. Pancreatic cancer cell lines were treated with tamoxifen, a novel antitumor fusicoccin derivative (ISIR-042), and anticancer drugs, and their effects on cell growth, signaling and gene expression were determined. Xenografts of Panc-1 cells were treated with tamoxifen, ISIR-042 and 5-fluorouracil (5FU) to determine the effects on tumor growth. The inhibition of the growth of pancreatic cancer cells induced by tamoxifen was effectively reduced by α-tocopherol, a membrane stabilizer. ISIR-042 produced synergistic effects with tamoxifen in inhibiting cell growth. Tamoxifen elevated lipid peroxidation and the release of cytochrome c, and these effects of tamoxifen were reduced by a-tocopherol. ISIR-042 significantly inhibited colony formation and the expression of sternness-related genes of pancreatic cancer cells. The triple combination of tamoxifen, ISIR-042, and 5FU or gemcitabine was effective at inhibiting cell growth and the appearance of drug-resistant cells. This combined treatment significantly inhibited the growth of Panc-1 cells as xenografts without apparent adverse effects. The triple combination of tamoxifen and ISIR-042 with 5FU or gemcitabine may be highly effective against pancreatic cancer by overcoming resistance to therapy.