p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin 1 in a highly metastatic mammary epithelial cell line: In vitro versus in vivo activity.

Abstract

We have evaluated the effects of bryostatin 1 on growth of a highly malignant p53-null mouse mammary tumor line, 4T1, and the mechanism by which bryostatin 1 inhibits in vitro growth and in vivo development of tumor and metastases from the orthotopic site. Bryostatin 1 at 20-400 nM concentrations inhibits growth of 4T1 cells by approximately 60% in two-day cultures. Inhibition of growth is associated with an increase in the number of cells undergoing apoptosis with concomitant elevation in the steady state levels of bax protein and drop in bcl-2 levels. The cytotoxic effect of bryostatin 1 on 4T1 cells occurs independently of p53, since there was no evidence of p53-mediated transcriptional activity in 4T1 cells following treatment with bryostatin 1.4T1 cells respond in vivo to bryostatin 1 therapy (75 microg/kg body weight). Intraperitoneal administration of bryostatin 1 inhibits both primary and secondary tumor growth by approximately 50%. However, although bryostatin 1 has a remarkable capacity to slow tumor growth and progression, it is unable to completely eradicate tumor growth and progression due to in vivo development of tumor resistance to bryostatin 1. Levels and cellular distribution of PKCalpha and delta do not correlate with the growth inhibitory effects of bryostatin 1 on 4T1 cells; however, reduction in cytosolic PKCalpha and delta without associated increase in membrane compartment appear to correlate with bryostatin-resistance. Our results suggest that the therapeutic effects of bryostatin 1 in our system do not involve alterations in levels and distribution of PKC but rather a direct upregulation of bax/ bcl-2 ratios that is independent of p53.

• Authors: H Wang, R M Mohammad, J Werdell, P V Shekhar
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 1 Issue 6 Pg. 915-23 (Jun 1998) ISSN: 1107-3756 [Print] Greece
• PMID: 9852625 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Bax protein, mouse
• Bryostatins
• DNA, Recombinant
• Isoenzymes
• Lactones
• Macrolides
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• bryostatin 1
• Prkca protein, mouse
• Protein Kinase C
• Protein Kinase C-alpha

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Bryostatins
• Cell Division (drug effects)
• DNA, Recombinant (genetics)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Vectors
• Isoenzymes (metabolism)
• Lactones (pharmacology)
• Lung Neoplasms (drug therapy, secondary)
• Macrolides
• Mammary Neoplasms, Experimental (drug therapy, pathology)
• Mice
• Mice, Inbred BALB C
• Mutation
• Neoplasm Metastasis
• Protein Kinase C (metabolism)
• Protein Kinase C-alpha
• Proto-Oncogene Proteins (drug effects, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics, physiology)
• bcl-2-Associated X Protein