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VMY-1-103, a dansylated analog of purvalanol B, induces caspase-3-dependent apoptosis in LNCaP prostate cancer cells.

Abstract
The 2,6,9-trisubstituted purine group of cyclin dependent kinase inhibitors have the potential to be clinically relevant inhibitors of cancer cell proliferation. We have recently designed and synthesized a novel dansylated analog of purvalanol B, termed VMY-1-103, that inhibited cell cycle progression in breast cancer cell lines more effectively than did purvalanol B and allowed for uptake analyses by fluorescence microscopy. ErbB-2 plays an important role in the regulation of signal transduction cascades in a number of epithelial tumors, including prostate cancer (PCa). Our previous studies demonstrated that transgenic expression of activated ErbB-2 in the mouse prostate initiated PCa and either the overexpression of ErbB-2 or the addition of the ErbB-2/ErbB-3 ligand, heregulin (HRG), induced cell cycle progression in the androgen-responsive prostate cancer cell line, LNCaP. In the present study, we tested the efficacy of VMY-1-103 in inhibiting HRG-induced cell proliferation in LNCaP prostate cancer cells. At concentrations as low as 1 μM, VMY-1-103 increased both the proportion of cells in G(1) and p21(CIP1) protein levels. At higher concentrations (5 μM or 10 μM), VMY-1-103 induced apoptosis via decreased mitochondrial membrane polarity and induction of p53 phosphorylation, caspase-3 activity and PARP cleavage. Treatment with 10 μM Purvalanol B failed to either influence proliferation or induce apoptosis. Our results demonstrate that VMY-1-103 was more effective in inducing apoptosis in PCa cells than its parent compound, purvalanol B, and support the testing of VMY-1-103 as a potential small molecule inhibitor of prostate cancer in vivo.
AuthorsLymor Ringer, Paul Sirajuddin, Venkata Mahidhar Yenugonda, Anup Ghosh, Kyle Divito, Valerie Trabosh, Yesha Patel, Amanda Brophy, Scott Grindrod, Michael P Lisanti, Dean Rosenthal, Milton L Brown, Maria Laura Avantaggiati, Olga Rodriguez, Chris Albanese
JournalCancer biology & therapy (Cancer Biol Ther) Vol. 10 Issue 4 Pg. 320-5 (Aug 15 2010) ISSN: 1555-8576 [Electronic] United States
PMID20574155 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 2-chloro-N-(2-(5-(dimethylamino)naphthalene-1-sulfonamido)ethyl)-4-(2-(1-hydroxy-3-methylbutan-2-ylamino)-9-isopropyl-9H-purin-6-ylamino)benzamide
  • Antineoplastic Agents
  • Dansyl Compounds
  • Tumor Suppressor Protein p53
  • Poly(ADP-ribose) Polymerases
  • p38 Mitogen-Activated Protein Kinases
  • Caspase 3
  • Adenine
Topics
  • Adenine (analogs & derivatives, chemistry, pharmacology)
  • Antineoplastic Agents (chemistry, pharmacology)
  • Apoptosis (drug effects)
  • Breast Neoplasms
  • Caspase 3 (metabolism)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Dansyl Compounds (chemistry, pharmacology)
  • Female
  • Flow Cytometry
  • Humans
  • Male
  • Mitochondrial Membranes (drug effects, metabolism)
  • Phosphorylation (drug effects)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Prostatic Neoplasms (drug therapy, metabolism, pathology)
  • Signal Transduction (drug effects)
  • Tumor Suppressor Protein p53 (metabolism)
  • p38 Mitogen-Activated Protein Kinases (metabolism)

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