Abstract | PURPOSE: EXPERIMENTAL DESIGN:
Mantle cell lymphoma (MCL), characterized by elevated cyclin D1, was used as a model to test this approach. The cyclin D/Rb/E2F1 pathway was investigated in vitro using MCL cell lines and primary tumor cells. Silvestrol was also evaluated in vivo using an aggressive model of MCL. RESULTS:
Silvestrol showed low nanomolar potency both in MCL cell lines and primary MCL tumor cells. D- cyclins were depleted with just 10 nmol/L silvestrol at 16 hours, with subsequent reductions of phosphorylated Rb, E2F1 protein, and E2F1 target transcription. As showed in other leukemias, silvestrol caused Mcl-1 depletion followed by mitochondrial depolarization and caspase-dependent apoptosis, effects not related to inhibition of CDK4/6. Silvestrol significantly (P < 0.0001) prolonged survival in a MCL xenograft model without detectable toxicity. CONCLUSIONS: These data indicate that silvestrol effectively targets the cyclin/CDK/Rb pathway, and additionally induces cytotoxicity via intrinsic apoptosis. This dual activity may be an effective therapeutic strategy in MCL and other malignancies.
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Authors | Lapo Alinari, Courtney J Prince, Ryan B Edwards, William H Towns, Rajeswaran Mani, Amy Lehman, Xiaoli Zhang, David Jarjoura, Li Pan, A Douglas Kinghorn, Michael R Grever, Robert A Baiocchi, David M Lucas |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 18
Issue 17
Pg. 4600-11
(Sep 01 2012)
ISSN: 1557-3265 [Electronic] United States |
PMID | 22791882
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | ©2012 AACR. |
Chemical References |
- E2F1 Transcription Factor
- Retinoblastoma Protein
- Triterpenes
- silvestrol
- Cyclin D1
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Topics |
- Animals
- Apoptosis
(drug effects, genetics)
- Cell Cycle
(drug effects, genetics)
- Cell Line, Tumor
- Cyclin D1
(genetics, metabolism)
- E2F1 Transcription Factor
(genetics, metabolism)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Lymphoma, Mantle-Cell
(genetics, metabolism, pathology, therapy)
- Metabolic Networks and Pathways
- Mice
- Mitochondria
(drug effects, metabolism)
- Retinoblastoma Protein
(genetics, metabolism)
- Signal Transduction
(drug effects)
- Transplantation, Heterologous
- Triterpenes
(pharmacology)
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