Abstracts: Abstracts of Papers Submitted to the 38th Annual Meeting of the American Pancreatic Association, November 1-3, 2007, Chicago, Illinois
TRIPTOLIDE INHIBITS TUMOR GROWTH AND LOCAL-REGIONAL SPREAD IN VIVO VIA INCREASED APOPTOSIS AND DECREASED HEAT SHOCK PROTEIN 70 (HSP70)
Pancreatic cancer has a high level of resistance to current chemotherapy agents. Overexpression of HSP70 in pancreatic cancer cells confers resistance to apoptosis and inhibition of HSP70 induces apoptosis in these cells.
To examine the effect of triptolide (a diterpenoid triepoxide) on: i) pancreatic cancer cell viability and apoptosis; ii) pancreatic cancer growth and local-invasion in vivo; and iii) HSP70 levels in vitro and in vivo.
Pancreatic cancer cells (MiaPaCa-2 and PANC-1) or normal pancreatic duct cells (PDC) were incubated with triptolide (100-200nM) or vehicle for 24h. Cell viability, apoptosis and HSP70 levels were assessed. We used an orthotopic model of pancreatic cancer by injecting MiaPaCa-2 cells into the pancreas; 6 days later we administered triptolide (0.2mg/kg/day) or vehicle for 60 days.
Triptolide significantly reduced pancreatic cancer cell viability, but had no effect on PDC viability (Triptolide 200nM - % of Control: MiaPaCa-2 56 ± 3, PANC-1 60 ± 2, PDC 85 ± 4). Triptolide induced apoptosis in the cancer cells as shown by increased Annexin V, caspase 3 (Table) and TUNEL. Triptolide decreased pancreatic cancer growth in vivo (Tumor cm3: Control 1.03 ± 0.43 vs Triptolide 0.14 ± 0.05, *p < 0.05, n ≥ 7, Mean ± SE), which was associated with increased apoptosis (TUNEL). Triptolide decreased local-regional spread (p < 0.001) to multiple organs compared to controls. Triptolide decreased HSP70 levels in vitro and in vivo compared to controls. (Table 1)
Triptolide causes pancreatic cancer cell death via apoptosis and its mechanism of action may be mediated by the inhibition of HSP70. Triptolide is a potential therapeutic agent to prevent the progression and invasion of pancreatic cancer.© 2007 Lippincott Williams & Wilkins, Inc.