The induction of senescence-like growth arrest by protein kinase C-activating diterpene esters in solid tumor cells

Mason, Sharon A., Cozzi, Sarah-Jane, Pierce, Carly J., Pavey, Sandra J., Parsons, Peter G. and Boyle, Glen M. (2010) The induction of senescence-like growth arrest by protein kinase C-activating diterpene esters in solid tumor cells. Investigational New Drugs, 28 5: 575-586. doi:10.1007/s10637-009-9292-y


Author Mason, Sharon A.
Cozzi, Sarah-Jane
Pierce, Carly J.
Pavey, Sandra J.
Parsons, Peter G.
Boyle, Glen M.
Title The induction of senescence-like growth arrest by protein kinase C-activating diterpene esters in solid tumor cells
Journal name Investigational New Drugs   Check publisher's open access policy
ISSN 0167-6997
1573-0646
Publication date 2010-10-01
Year available 2009
Sub-type Article (original research)
DOI 10.1007/s10637-009-9292-y
Open Access Status DOI
Volume 28
Issue 5
Start page 575
End page 586
Total pages 12
Place of publication New York, NY, United States
Publisher Springer New York LLC
Language eng
Abstract We previously identified the induction of senescence in melanoma cell lines sensitive to diterpene esters, indicating a therapeutic potential. Here we compared the cytostatic effects of two diterpene esters: the prototypic PKC-activating drug TPA (12-O-tetradecanoylphorbol-13-acetate), and the novel compound PEP008 (20-O-acetyl-ingenol-3-angelate) in cell lines derived from melanoma, breast cancer and colon cancer. The diterpene esters induced permanent growth arrest with characteristics of senescence in a subset of cell lines in all three solid tumor models at 100-1000 ng/ml. Use of the PKC inhibitor bisindolylmaleimide-l demonstrated that activation of PKC was required for growth arrest. Full genome expression profiling identified pivotal genes involved in DNA synthesis and cell cycle control down-regulated by treatment in all three sensitive tumor models. At the protein level, prolonged down-regulation of E2F-1 and proliferating cell nuclear antigen (PCNA), sustained expression of p21(WAF1/CIP1) and dephosphorylation of retinoblastoma (Rb) occurred in the sensitive cells. Additionally, the type II tumor suppressor HRASLS3, which has a role in mitogen-activated protein kinase (MAPK) pathway suppression, was constitutively elevated in cell lines resistant to the senescence effects compared to their sensitive counterparts. Together, these results demonstrate that both TPA and the novel PKC-activating drug PEP008 induce growth arrest with characteristics of senescence in solid tumor cell lines derived from a variety of tissue types, and by a similar mechanism. PKC-activating diterpene esters may therefore have therapeutic potential in a subset of breast cancer, colon cancer and melanoma tumors.
Formatted abstract
We previously identified the induction of senescence in melanoma cell lines sensitive to diterpene esters, indicating a therapeutic potential. Here we compared the cytostatic effects of two diterpene esters: the prototypic PKC-activating drug TPA (12-O-tetradecanoylphorbol-13-acetate), and the novel compound PEP008 (20-O-acetyl-ingenol-3-angelate) in cell lines derived from melanoma, breast cancer and colon cancer. The diterpene esters induced permanent growth arrest with characteristics of senescence in a subset of cell lines in all three solid tumor models at 100-1000 ng/ml. Use of the PKC inhibitor bisindolylmaleimide-l demonstrated that activation of PKC was required for growth arrest. Full genome expression profiling identified pivotal genes involved in DNA synthesis and cell cycle control down-regulated by treatment in all three sensitive tumor models. At the protein level, prolonged down-regulation of E2F-1 and proliferating cell nuclear antigen (PCNA), sustained expression of p21WAF1/CIP1 and dephosphorylation of retinoblastoma (Rb) occurred in the sensitive cells. Additionally, the type II tumor suppressor HRASLS3, which has a role in mitogen-activated protein kinase (MAPK) pathway suppression, was constitutively elevated in cell lines resistant to the senescence effects compared to their sensitive counterparts. Together, these results demonstrate that both TPA and the novel PKC-activating drug PEP008 induce growth arrest with characteristics of senescence in solid tumor cell lines derived from a variety of tissue types, and by a similar mechanism. PKC-activating diterpene esters may therefore have therapeutic potential in a subset of breast cancer, colon cancer and melanoma tumors.
© 2009 Springer Science+Business Media, LLC.
Keyword Diterpene ester
Senescence
PKC
TPA
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 552440
199600
Institutional Status UQ
Additional Notes Published online: 28 July 2009

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
 
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Created: Wed, 30 Mar 2011, 21:41:04 EST by Lisa Hennell on behalf of UQ Diamantina Institute