Enhanced Antitumor Effect of Combination Therapy With Gemcitabine and Guggulsterone in Pancreatic Cancer

Objectives: Guggulsterone is a dietary plant sterone possessing therapeutic potential against cancers. However, the antitumor effect of this natural compound on pancreatic cancer has not been determined yet. This study was designed to investigate the therapeutic efficacy of guggulsterone in pancreatic cancer. Methods: In this study, we examined the effect of guggulsterone on cell proliferation and apoptosis in pancreatic cancer cell lines, and then, we investigated the mechanisms responsible for the effect of guggulsterone. Finally, we investigated whether the combination of guggulsterone and gemcitabine had an additional therapeutic effect compared to gemcitabine single regimen in pancreatic cancer cell lines (in vitro) and in a xenograft model using nude mice (in vivo). Results: In vitro, the combination treatment resulted in more growth inhibition and apoptosis through the down-regulation of nuclear factor kappa B activity with suppression of Akt and BcL-2 and through the activation of c-Jun NH2-terminal kinase and Bax in pancreatic cancer cell lines. In vivo, the combination therapy augmented tumor growth inhibition through the same mechanisms in tumor tissue. Conclusions: The combination of guggulsterone to gemcitabine enhanced antitumor efficacy through apoptosis induction by suppressing Akt and nuclear factor kappa B activity and by modulating apoptosis-related protein expression in pancreatic cancer.