Vetrichelvan Jayaprakasan

Publications (2)11.23 Total impact

• Article: Restoring chemotherapy and hormone therapy sensitivity by parthenolide in a xenograft hormone refractory prostate cancer model.

  Rajasubramaniam Shanmugam, Vetrichelvan Jayaprakasan, Yesim Gokmen-Polar, Stephanie Kelich, Kathy D Miller, Michele Yip-Schneider, Liang Cheng, Poornima Bhat-Nakshatri, George W Sledge, Harikrishna Nakshatri, Qi-Huang Zheng, Michael A Miller, Timothy DeGrado, Gary D Hutchins, Christopher J Sweeney
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  ABSTRACT: Nuclear Factor kappa B (NFkappaB) is a eukaryotic transcription factor that is constitutively active in human cancers and can be inhibited by the naturally occurring sesquiterpene lactone, parthenolide (P). The in vitro effects of P were assessed using the androgen independent cell line, CWR22Rv1, and human umbilical endothelial cells (HUVECs). The in vivo activity of P as a single agent and its ability to augment the efficacy of docetaxel and the anti-androgen, bicalutamide, were determined using the CWR22Rv1 xenograft model. Parthenolide at low micromolar concentration inhibited proliferation of CWR22Rv1 and HUVEC cells, promoted apoptosis and abrogated NFkappaB-DNA binding. Parthenolide downregulated anti-apoptotic genes under NFkappaB control, TRAF 1 and 2, and promoted sustained activation of c-jun-NH2 kinase (JNK). Parthenolide also augmented the in vivo efficacy of docetaxel and restored sensitivity to anti-androgen therapy. These studies demonstrate parthenolide's anti-tumor and anti-angiogenic activity, and its potential to augment the efficacy of chemotherapy and hormonal therapy.
  The Prostate 11/2006; 66(14):1498-511. · 3.48 Impact Factor
• Article: Nuclear factor-kappaB is constitutively activated in prostate cancer in vitro and is overexpressed in prostatic intraepithelial neoplasia and adenocarcinoma of the prostate.

  Christopher Sweeney, Lang Li, Rajasubramaniam Shanmugam, Poornima Bhat-Nakshatri, Vetrichelvan Jayaprakasan, Lee Ann Baldridge, Thomas Gardner, Martin Smith, Harikrishna Nakshatri, Liang Cheng
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  ABSTRACT: The transcription factor nuclear factor-kappaB (NF-kappaB) promotes the production of angiogenic, antiapoptotic, and prometastatic factors that are involved in carcinogenesis. Electromobility gel shift assays were used to evaluate NF-kappaB DNA binding in vitro. The functional relevance of NF-kappaB DNA binding was assessed by both cDNA array analyses and proliferation assays of prostate cancer cells with and without exposure to an NF-kappaB inhibitor, parthenolide. Immunohistochemistry staining for the p65 NF-kappaB subunit was used to determine the frequency and location of NF-kappaB in 97 prostatectomy specimens. The amount of staining was quantified on a 0-3+ scale. An electromobility gel shift assay confirmed the presence of NFkappaB DNA binding in all four prostate cancer cell lines tested. The binding was inhibited by parthenolide, and this agent also decreased multiple gene transcripts under the control of NF-kappaB and inhibited proliferation of prostate cancer cells. The staining results revealed overexpression of p65 in the prostatic intraepithelial neoplasia and cancer compared with the benign epithelium. Specifically, there was a predominance of 1+ and 2+ with no 3+ staining in benign epithelium, whereas there was only 2+ and 3+ staining (30 and 70%, respectively) in the cancerous areas. These differences were statistically different. There was no correlation with tumor grade or stage. NF-kappaB is constitutively activated in prostate cancer and functionally relevant in vitro. Immunohistochemistry of human prostatectomy specimens demonstrated overexpression of the active subunit of NF-kappaB, p65, and that this occurs at an early stage in the genesis of prostate cancer. This work supports the rationale for targeting NF-kappaB for the prevention and/or treatment of prostate cancer.
  Clinical Cancer Research 09/2004; 10(16):5501-7. · 7.74 Impact Factor