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Authors: Lymor Ringer, Paul Sirajuddin, Venkata Mahidhar Yenugonda, Anup Ghosh, Kyle Divito, Valerie Trabosh, Yesha Patel, Amanda Brophy, Scott Grindrod, Michael P. Lisanti, Milton L. Brown, Maria Laura Avantaggiati, Olga C. Rodriguez and Chris Albanese

Lymor Ringer

Georgetown University Medical Center; Washington, DC

Paul Sirajuddin

Georgetown University Medical Center; Washington, DC

Venkata Mahidhar Yenugonda

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

Anup Ghosh

Georgetown University Medical Center; Washington, DC

Kyle Divito

Department of Oncology and Drug Discovery Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

Valerie Trabosh

Drug Discovery Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

Yesha Patel

Marshall University Medical School, Huntington, W.V.

Amanda Brophy

Georgetown University Medical Center; Washington, DC

Scott Grindrod

Department of Oncology and Drug Discovery Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

Michael P. Lisanti

Thomas Jefferson University

Milton L. Brown

Department of Oncology and Drug Discovery Program, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA

Maria Laura Avantaggiati

Georgetown University Medical Center; Washington, DC

Olga C. Rodriguez

Lombardi Cancer Comprehensive Center, Georgetown University Medical Center; Washington DC USA

Chris Albanese

Corresponding author: Albanese@georgetown.edu
Georgetown University Medical Center; Washington DC USA

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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 G1 and p21CIP1 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.