Smac mimetic-derived augmentation of chemotherapeutic response in experimental pancreatic cancer
1 Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center Dallas, TX 75390, USA
2 Department of Pediatrics, The University of Texas Southwestern Medical Center Dallas, TX 75390
3 Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center Dallas, TX 75390
4 Department of Pharmacology The University of Texas Southwestern Medical Center Dallas, TX 75390
BMC Cancer 2011, 11:15 doi:10.1186/1471-2407-11-15Published: 12 January 2011
Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to conventional chemotherapy, in part due to the overexpression of inhibitors of apoptosis proteins (IAPs). Smac is an endogenous IAP-antagonist, which renders synthetic Smac mimetics attractive anticancer agents. We evaluated the benefits of combining a Smac mimetic, JP1201 (JP), with conventional chemotherapy agents used for PDAC management.
Cell viability assays and protein expression analysis were performed using WST-1 reagent and Western blotting, respectively. Apoptosis was detected by annexin V/propidium iodide staining. In vivo tumor growth and survival studies were performed in murine PDAC xenografts.
JP and gemcitabine (Gem) inhibited PDAC cell proliferation with additive effects in combination. The percentage of early apoptotic cells in controls, JP, Gem and JP + Gem was 17%, 26%, 26% and 38%, respectively. JP-induced apoptosis was accompanied by PARP-1 cleavage. Similar additive anti-proliferative effects were seen for combinations of JP with doxorubicin (Dox) and docetaxel (DT). The JP + Gem combination caused a 30% decrease in tumor size in vivo compared to controls. Median animal survival was improved significantly in mice treated with JP + Gem (38 d) compared to controls (22 d), JP (28 d) or Gem (32 d) (p = 0.01). Animal survival was also improved with JP + DT treatment (32 d) compared to controls (16 d), JP (21 d) or DT alone (27 d).
These results warrant further exploration of strategies that promote chemotherapy-induced apoptosis of tumors and highlight the potential of Smac mimetics in clinical PDAC therapy.