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

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-KB (NF-KB) has been linked with inflammatory diseases, including insulin resistance, we hypothesized that pinitol must mediate its effects through modulation of NF-KB activation pathway. We found that pinitol suppressed NF-KB activation induced by inflammatory stimuli and carcinogens. This suppression was not specific to cell type. Besides inducible, pinitol also abrogated constitutive NF-KB activation noted in most tumor cells. The suppression of NF-KB activation by pinitol occurred through inhibition of the activation of IKBA kinase, leading to sequential suppression of IKBA phosphorylation, IKBA degradation, p65 phosphorylation, p65 nuclear translocation, and NF-KB-dependent reporter gene expression. Pinitol also suppressed the NF-KB reporter activity induced by tumor necrosis factor receptor (TNFR)-1, TNFR-associated death domain, TNFR-associated factor-2, transforming growth factor-B -activated kinase-1 (TAK-1)/TAK1-binding protein-1, and IKBA kinase but not that induced by p65. The inhibition of NF-KB 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 TNFinduced cellular invasion. Our results show that pinitol inhibits the NF-KB activation pathway, which may explain its ability to suppress inflammatory cellular responses.

Cyclitols in maturing grains of wheat, triticale and barley

“…On the other hand, D-pinitol and D-chiro-inositol indicate some health benefits both cyclitols and their galactosides can be helpful compounds in treatment of type 2 diabetes (lowering glucose level in blood), polycystic ovary syndrome (Yoshida et al 2006), and Alzheimers disease (Nitz et al 2008). Pinitol also possesses anti-inflammatory (Sethi et al 2008) and anti-viral properties (Zhan et al 2006) and has been implicated in the prevention of cardiovascular diseases (Choi et al 2009). The latter suggests that D-pinitol can act as a potential anti-tumor agent (Sethi et al 2008;Zhan and Lou 2007).…”

“…Pinitol also possesses anti-inflammatory (Sethi et al 2008) and anti-viral properties (Zhan et al 2006) and has been implicated in the prevention of cardiovascular diseases (Choi et al 2009). The latter suggests that D-pinitol can act as a potential anti-tumor agent (Sethi et al 2008;Zhan and Lou 2007). Thus, it can be hypothesised that the presence of some cyclitols in cereal grains can improve health promoting properties.…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[157] It also suppresses inflammation-and carcinogen-induced activation of NF-κB leading to the reduced expression of a number of genes involved in proliferation, apoptosis, invasion and angiogenesis. [158] Pinitol reduces osteoclastogenesis by inhibiting the receptor activator of NF-κB ligand (RANKL). [159] By reducing the cell surface expression of αvβ3 integrin and inhibiting focal adhesion kinase phosphorylation, c-Src kinase activity and NF-κB activation pinitol inhibits prostate cancer metastasis.…”

Pinitol suppresses tumor necrosis factor-α-induced invasion of prostate cancer LNCaP cells by inhibiting nuclear factor-κB-Mediated matrix Metalloproteinase-9 expression

“…Pinitol, traditionally used in Ayurvedic medicine and extracted from plants such as Bougainvillea spectabilis, has been shown to exhibit antiinflammatory and antidiabetic activities, inhibit the T-helper cell-1 response, and prevent cardiovascular diseases [11][12][13]. Pinitol appears to regulate the effects of insulin by targeting downstream in the insulin signaling pathway, suggesting that pinitol possesses hypoglycemic activity [14].…”

“…Pinitol appears to regulate the effects of insulin by targeting downstream in the insulin signaling pathway, suggesting that pinitol possesses hypoglycemic activity [14]. Pinitol also triggers apoptotic cascades in human breast cancer cells by inducing the expression of tumor suppressor genes [12]. However, little is known about the effects of pinitol on the expression and invasion of MMP-9 in prostate cancer cells.…”