Induction of growth inhibition and apoptosis in pancreatic cancer cells by auristatin-PE and gemcitabine.

Abstract

Pancreatic adenocarcinoma is the fifth leading cause of cancer related deaths in the United States. Treatment for this disease has largely been unsuccessful, which may partly be due to insufficient data regarding the molecular mechanisms of chemotherapeutic drugs currently being used as single agents or in combined modality regimens. In this study, we investigated the molecular mechanisms by which auristatin-PE, a newly developed experimental agent, and gemcitabine, a commercially available anti-cancer agent, exert their inhibitory effects on pancreatic cancer cell lines containing wild-type p53 (HPAC) and mutant p53 (PANC-1). Our results showed that auristatin-PE and gemcitabine inhibited cell growth and induced cell cycle arrest in G2/M and S phase, respectively. Auristatin-PE also induced apoptosis in both cell lines. Western blot analysis showed that auristatin-PE up-regulated the expression of wt-p53, p21WAF1 and Bax, and down-regulated Bcl-2 and cyclin B in HPAC cells, while only up-regulation of p21WAF1 and Bax was observed in PANC-1 cells. These results suggest that auristatin-PE may induce apoptosis and p21WAF1 expression through p53-dependent or independent pathways, and that up-regulation of p21WAF1 and Bax and down-regulation of Bcl-2 may be the molecular mechanism through which auristatin-PE inhibits cell growth and induces apoptosis. Furthermore, the up-regulation of p21WAF1 and down-regulation of cyclin B may contribute to the G2/M cell cycle arrest. Combination of auristatin-PE and gemcitabine showed significantly greater inhibition of cell growth and up-regulated expression of p21WAF1 and Bax. From these results, we conclude that the selection of therapeutic agents based on their molecular mechanism may improve therapeutic outcome, and that auristatin-PE may be more effective in the treatment of pancreatic cancer when given in combination with gemcitabine, rather than as a single agent.

• Authors: Y Li, B Singh, N Ali, F H Sarkar
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 3 Issue 6 Pg. 647-53 (Jun 1999) ISSN: 1107-3756 [Print] Greece
• PMID: 10341297 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BAX protein, human
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Oligopeptides
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• Deoxycytidine
• soblidotin
• Gemcitabine

Topics

• Adenocarcinoma (metabolism, pathology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (biosynthesis)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Flow Cytometry
• Gene Expression (drug effects)
• Humans
• Oligopeptides (pharmacology)
• Pancreatic Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins (biosynthesis)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (biosynthesis)
• bcl-2-Associated X Protein
• Gemcitabine