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Alpha-tomatine attenuation of in vivo growth of subcutaneous and orthotopic xenograft tumors of human prostate carcinoma PC-3 cells is accompanied by inactivation of nuclear factor-kappa B signaling.

AbstractBACKGROUND:
Nuclear factor-kappa B (NF-κB) plays a role in prostate cancer and agents that suppress its activation may inhibit development or progression of this malignancy. Alpha (α)-tomatine is the major saponin present in tomato (Lycopersicon esculentum) and we have previously reported that it suppresses tumor necrosis factor-alpha (TNF-α)-induced nuclear translocation of nuclear factor-kappa B (NF-κB) in androgen-independent prostate cancer PC-3 cells and also potently induces apoptosis of these cells. However, the precise mechanism by which α-tomatine suppresses NF-κB nuclear translocation is yet to be elucidated and the anti-tumor activity of this agent in vivo has not been examined.
METHODOLOGY/PRINCIPAL FINDINGS:
In the present study we show that suppression of NF-κB activation by α-tomatine occurs through inhibition of I kappa B alpha (IκBα) kinase activity, leading to sequential suppression of IκBα phosphorylation, IκBα degradation, NF-κB/p65 phosphorylation, and NF-κB p50/p65 nuclear translocation. Consistent with its ability to induce apoptosis, α-tomatine reduced TNF-α induced activation of the pro-survival mediator Akt and its inhibition of NF-κB activation was accompanied by significant reduction in the expression of NF-κB-dependent anti-apoptotic (c-IAP1, c-IAP2, Bcl-2, Bcl-xL, XIAP and survivin) proteins. We also evaluated the antitumor activity of α-tomatine against PC-3 cell tumors grown subcutaneously and orthotopically in mice. Our data indicate that intraperitoneal administration of α-tomatine significantly attenuates the growth of PC-3 cell tumors grown at both sites. Analysis of tumor material indicates that the tumor suppressing effects of α-tomatine were accompanied by increased apoptosis and lower proliferation of tumor cells as well as reduced nuclear translocation of the p50 and p65 components of NF-κB.
CONCLUSION/SIGNIFICANCE:
Our study provides first evidence for in vivo antitumor efficacy of α-tomatine against the human androgen-independent prostate cancer. The potential usefulness of α-tomatine in prostate cancer prevention and therapy requires further investigation.
AuthorsSui-Ting Lee, Pooi-Fong Wong, Hui He, John David Hooper, Mohd Rais Mustafa
JournalPloS one (PLoS One) Vol. 8 Issue 2 Pg. e57708 ( 2013) ISSN: 1932-6203 [Electronic] United States
PMID23437404 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents, Phytogenic
  • Apoptosis Regulatory Proteins
  • NF-kappa B
  • Protein Subunits
  • alpha-tomatine
  • Tomatine
  • I-kappa B Kinase
Topics
  • Adenocarcinoma (drug therapy, genetics, metabolism, pathology)
  • Animals
  • Antineoplastic Agents, Phytogenic (pharmacology)
  • Apoptosis (drug effects)
  • Apoptosis Regulatory Proteins (antagonists & inhibitors, genetics, metabolism)
  • Cell Proliferation (drug effects)
  • Choristoma
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • I-kappa B Kinase (antagonists & inhibitors, genetics, metabolism)
  • Male
  • Mice
  • NF-kappa B (antagonists & inhibitors, genetics, metabolism)
  • Neoplasm Transplantation
  • Phosphorylation (drug effects)
  • Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
  • Protein Subunits (antagonists & inhibitors, genetics, metabolism)
  • Protein Transport (drug effects)
  • Signal Transduction (drug effects)
  • Tomatine (analogs & derivatives, pharmacology)

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