Abstract
BackgroundPancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer.MethodsThe effects of gambogic acid on cell viability, the cell cycle, and apoptosis were assessed using 4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and flow cytometry in pancreatic cancer cell lines. Protein expression was detected by western blot analysis and mRNA expression was detected using q-PCR. A xenograft tumor model of pancreatic cancer was used to investigate the synergistic effects of gambogic acid and gemcitabine.ResultsGambogic acid effectively inhibited the growth of pancreatic cancer cell lines by inducing S-phase cell cycle arrest and apoptosis. Synergistic activity of gambogic acid combined with gemcitabine was observed in PANC-1 and BxPC-3 cells based on the results of MTT, colony formation, and apoptosis assays. Western blot results demonstrated that gambogic acid sensitized gemcitabine-induced apoptosis by enhancing the expression of cleaved caspase-3, cleaved caspase-9, cleaved-PARP, and Bax, and reducing the expression of Bcl-2. In particular, gambogic acid reduced the expression of the ribonucleotide reductase subunit-M2 (RRM2) protein and mRNA, a trend that correlated with resistance to gemcitabine through inhibition of the extracellular signal-regulated kinase (ERK)/E2F1 signaling pathway. Treatment with gambogic acid and gemcitabine significantly repressed tumor growth in the xenograft pancreatic cancer model. Immunohistochemistry results demonstrated a downregulation of p-ERK, E2F1, and RRM2 in mice receiving gambogic acid treatment and combination treatment.ConclusionsThese results demonstrate that gambogic acid sensitizes pancreatic cancer cells to gemcitabine in vitro and in vivo by inhibiting the activation of the ERK/E2F1/RRM2 signaling pathway. The results also indicate that gambogic acid treatment combined with gemcitabine might be a promising chemotherapy strategy for pancreatic cancer.
Highlights
Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy
Gambogic acid and gemcitabine act synergistically against pancreatic cancer cells in vitro by inducing apoptosis As ribonucleotide reductase subunit-M2 (RRM2) expression was inhibited by gambogic acid (GA), and RRM2 was associated with gemcitabine resistance, we investigated whether GA combined with gemcitabine had a synergistic effect against pancreatic cancer cells
Previous studies suggest that RRM1 and RRM2 could predict the prognosis of patients treated with gemcitabine, as they report that relatively high expression of these two genes in pancreatic cancer is associated with a poor prognosis, and patients who do not benefit from gemcitabine treatment tend to have elevated RRM1 and RRM2 expression [42, 43]
Summary
Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Chemotherapy improves the prognosis in pancreatic cancer patients, the five-year survival rate remains less than 5% [1,2,3]. Albumin-bound paclitaxel combined with gemcitabine improves survival in patients with advanced pancreatic cancer; those patients had little survival benefit, companied by serious side effects [6, 7]. Exploration of a novel drug that can be used in combination with gemcitabine is crucial to improving both the therapeutic effects of gemcitabine in pancreatic cancer patients and the prognosis in such patients. Previous studies have found that the expression of RRM1 and RRM2 in pancreatic cancer cells increases their sensitivity to gemcitabine [11,12,13]. RRM1 acts as a tumor suppressor gene that inhibits tumor cell growth and metastasis by inducing the expression of the tumor suppressor gene PTEN in lung cancer [17]
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