Enhanced effect of gemcitabine by emodin against pancreatic cancer in vivo via cytochrome C-regulated apoptosis.

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.

• Authors: Hui Chen, Weitian Wei, Yafei Guo, An Liu, Hongfei Tong, Zhaohong Wang, Wei Tan, Jinxiang Liu, Shengzhang Lin
• Journal: Oncology reports (Oncol Rep) Vol. 25 Issue 5 Pg. 1253-61 (May 2011) ISSN: 1791-2431 [Electronic] Greece
• PMID: 21305255 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• Deoxycytidine
• Cytochromes c
• Caspase 3
• Emodin
• Gemcitabine

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytochromes c (metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• Drug Synergism
• Emodin (pharmacology, therapeutic use)
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, pathology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (metabolism)
• Gemcitabine