Abstract. Pancreatic adenocarcinoma is one of the most common malignancies worldwide. Gemcitabine is currently the standard first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine can induce activation of Akt and nuclear factor-κB (NF-κB), which is associated with its chemoresistance. It has been reported that gemcitabine combination therapies result in improved survival outcomes in pancreatic cancer. Therefore, agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Emodin is an active component of Chinese medicinal herbs and can inhibit the activation of Akt and NF-κB. In this study, we investigated whether emodin could enhance the anticancer effect of gemcitabine on pancreatic cancer in vivo. We demonstrated that treatment of gemcitabine combined with emodin efficiently suppressed tumor growth in mice inoculated with pancreatic tumor cells. This treatment paradigm promoted apoptotic cell death and mitochondrial fragmentation. Furthermore, it reduced phosphorylated-Akt (p-Akt) level, NF-κB activation and Bcl-2/Bax ratio, increased caspase-9 and -3 activation, Cytochrome C (CytC) release occurred in combination therapy. Collectively, emodin enhanced the activity of gemcitabine in tumor growth suppression via inhibition of Akt and NF-κB activation, thus promoting the mitochondrial-dependent apoptotic pathway. Therefore, our findings may provide new insights into understanding the pharmacological regulation of emodin on gemcitabine-mediated proapoptosis in pancreatic cancer and may aid in the design of new therapeutic strategies for the intervention of human pancreatic cancers.

Abstract. gemcitabine is currently the best treatment available for pancreatic cancer, but causes high toxicity. Agents that can enhance the effects of gemcitabine with no or low toxicity are needed for the treatment of pancreatic cancer. emodin, a natural anthraquinone derivative, is one such agent that has been shown to induce apoptosis in other tumor cells via down-regulation of Bcl-2/Bax and promoting the release of cytochrome c (cytc), but with very low toxicity. the aim of this study was to evaluate whether emodin can enhance the effect of gemcitabine on pancreatic cancer in vitro and in vivo and to investigate the possible mechanisms of the enhancement. In vitro, emodin inhibited the proliferation of the sW1990 cell line and potentiated the apoptosis induced by gemcitabine, which was demonstrated by activation of caspase-3 in the combination group. In vivo, tumors from nude mice subcutaneously injected with sW1990 cells and treated with a combination of emodin (40 mg/kg) and gemcitabine (80 mg/ kg) showed significant reductions in volume, Ki-67 proliferation index and expression of the Bcl-2/Bax ratio (compared with tumors from mice treated with sodium chloride, emodin alone (40 mg/kg) or gemcitabine alone (125 mg/kg), which induced increasing release of cytc from the mitochondria to the cytoplasm and triggered caspase-3 activation leading to apoptosis. taken together, our results suggest that emodin improved the anti-tumor effect of gemcitabine, even at a lower dose of gemcitabine which could decrease the toxicity of chemotherapy, on transplanted tumors of the sW1990 cell line through the enhancement of apoptosis induced by gemcitabine, the mechanism of which may be through down-regulation of the Bcl-2/Bax ratio and promoting release of cytc from the mitochondria into the cytoplasm.

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