Glaucarubinone Combined with Gemcitabine Improves Pancreatic Cancer Survival in an Immunocompetent Orthotopic Murine Model

ABSTRACT

Background: Pancreatic cancer continues to have a poor survival rate with an urgent need for improved treatments. Glaucarubinone, a natural product first isolated from the seeds of the tree Simarouba glauca, has recently been recognized as having anti-cancer properties that may be particularly applicable to pancreatic cancer. Methods: The effect of glaucarubinone on the growth and migration of murine pancreatic cancer cells was assessed by ³H-thymidine incorporation assay. The survival impact of glaucarubinone alone and in combination with gemcitabine chemotherapy was assessed using an immunocompetent orthotopic murine model of pancreatic cancer. Results: Glaucarubinone inhibited the growth of the murine pancreatic cancer cell lines LM-P and PAN02. Treatment with either glaucarubinone or gemcitabine reduced proliferation in vitro and the combination was synergistic. The combination treatment improved survival two-fold compared to gemcitabine treatment alone (p = 0.046) in PAN02 cells. Conclusions: The synergistic inhibition by glaucarubinone and gemcitabine observed in vitro and the improved survival in vivo suggest that glaucarubinone may be a useful adjunct to current chemotherapy regimens.

Keywords: :

• glaucarubinone
• gemcitabine
• pancreatic cancer
• survival

ACKNOWLEDGMENTS

We thank the Drug Synthesis & Chemistry Branch, NCI, for supplying the glaucarubinone used in this study.

FUNDING

This work was supported by grants from the Austin Hospital Medical Research Foundation, the Sir Edward Dunlop Foundation, and the National Health of Medical Research Council (NHMRC) of Australia (1020983, GSB; 508908, HH). Dannel Yeo is supported by Australian Rotary Health (The Ian Loxton Pancreatic Cancer Research PhD Scholarship). We also acknowledge the funding support of the Pancare Foundation (www.pancare.org.au) provided to develop novel therapies for the treatment of pancreatic cancer.