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Research Articles: Therapeutics, Targets, and Development

Pinitol targets nuclear factor-B activation pathway leading to inhibition of gene products associated with proliferation, apoptosis, invasion, and angiogenesis

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3503 Fax: 713-794-1613. E-mail: aggarwal{at}mdanderson.org

Abstract

Pinitol (3-O-methyl-chiroinositol), a component of traditional Ayurvedic medicine (talisapatra), has been shown to exhibit anti-inflammatory and antidiabetic activities through undefined mechanisms. Because the transcription factor nuclear factor-B (NF-B) has been linked with inflammatory diseases, including insulin resistance, we hypothesized that pinitol must mediate its effects through modulation of NF-B activation pathway. We found that pinitol suppressed NF-B activation induced by inflammatory stimuli and carcinogens. This suppression was not specific to cell type. Besides inducible, pinitol also abrogated constitutive NF-B activation noted in most tumor cells. The suppression of NF-B activation by pinitol occurred through inhibition of the activation of IB kinase, leading to sequential suppression of IB phosphorylation, IB degradation, p65 phosphorylation, p65 nuclear translocation, and NF-B-dependent reporter gene expression. Pinitol also suppressed the NF-B reporter activity induced by tumor necrosis factor receptor (TNFR)-1, TNFR-associated death domain, TNFR-associated factor-2, transforming growth factor-β–activated kinase-1 (TAK-1)/TAK1-binding protein-1, and IB kinase but not that induced by p65. The inhibition of NF-B activation thereby led to down-regulation of gene products involved in inflammation (cyclooxygenase-2), proliferation (cyclin D1 and c-myc), invasion (matrix metalloproteinase-9), angiogenesis (vascular endothelial growth factor), and cell survival (cIAP1, cIAP2, X-linked inhibitor apoptosis protein, Bcl-2, and Bcl-xL). Suppression of these gene products by pinitol enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed TNF-induced cellular invasion. Our results show that pinitol inhibits the NF-B activation pathway, which may explain its ability to suppress inflammatory cellular responses. [Mol Cancer Ther 2008;7(6):1604–14]

Grant support: Clayton Foundation for Research (B.B. Aggarwal) and NIH Core grant 5P30 CA016672-32 for flow cytometry analysis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: B.B. Aggarwal is Ransom Horne, Jr., Professor of Cancer Research.

Received 12/26/07; revised 2/25/08; accepted 3/11/08.