Inhibition of IGF-1R and lipoxygenase by nordihydroguaiaretic acid (NDGA) analogs

Abstract

Herein we pursue the hypothesis that the structure of nordihydroguaiaretic acid (NDGA) can be refined for selective potency against the insulin-like growth factor 1 receptor (IGF-1R) as a potential therapeutic target for breast cancer while diminishing its action against other cellular targets. Thus, a set of NDGA analogs (7a-7h) was prepared and examined for inhibitory potency against IGF-1R kinase and an alternative target, 15-lipoxygenase (15 LOX). The anti-cancer effects of these compounds were determined by their ability to inhibit IGF-1 mediated cell growth of MCF-7 breast cancer cells. The design of the analogs was based upon a cursory Topliss approach in which one of NDGA's aromatic rings was modified with various substituents. Structural modification of one of the two catechol rings of NDGA was found to have little effect upon the inhibitory potency against both kinase activity of the IGF-1R and IGF-1 mediated cell growth of MCF-7 cells. 15-LOX was found to be most sensitive to structural modifications of NDGA. From the limited series of NDGA analogs examined, the compound that exhibited the greatest selectivity for IGF-1 mediated growth compared to 15-LOX inhibition was a cyclic analog 7h with a framework similar to a natural product isolated from Larrea divaricata. The results for 7h are significant because while NDGA displays biological promiscuity, 7h exhibits greater specificity towards the breast cancer target IGF-1R with that added benefit of possessing a 10-fold weaker potency against 15-LOX, an enzyme which has a purported tumor suppressing role in breast cancer. With increased specificity and potency, 7h may serve as a new lead in developing novel therapeutic agents for breast cancer.Nordihydroguaiaretic acid (NDGA, Figure 1) is isolated from the resinous extract of the creosote bush Larrea divaricata. 1 It has also been reported that NDGA inhibits the growth of tumors, both in vitro and in vivo 2 but relatively high concentrations are required to achieve efficacy in most cases. Preliminary in vivo studies have revealed that NDGA inhibits tumor growth by inhibiting receptor tyrosine kinase (RTK) phosphorylation. 3 NDGA has been shown to inhibit several RTKs overexpressed in certain cancer cells. In a previous study, we noted that NDGA inhibits both the IGF-1R and HER2/neu with moderate potency and impairs subsequent signaling through the anti-apoptotic pathway in breast cancer cell. 3, 4 These and other RTKs such as the epidermal growth factor receptor (EGFR) are overexpressed in breast and other cancers and contribute to a poor prognosis 5-7 .Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal ...

GABABReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

“…5B) and NDGA (7H) (supplemental Fig. 1A, available at www.jneurosci.org as supplemental material) (Blecha et al, 2007).…”

Antioxidant Activity of Butane Type Lignans, Secoisolariciresinol, Dihydroguaiaretic Acid, and 7,7′-Oxodihydroguaiaretic Acid

“…The lipoprotein-antioxidant activity of isolated 2 0 -hydroxy dihydroguaiaretic acid 7) and lipoxygenase inhibition of nordihydroguaiaretic acid (NDGA) have been reported. 8) However, the effect of stereochemistry has not been described. The oxidation enzyme-antioxidant activity of the enantiomers is compared in this report for the first time.…”

Cannabidiol-2′,6′-Dimethyl Ether, a Cannabidiol Derivative, Is a Highly Potent and Selective 15-Lipoxygenase Inhibitor

“…1A), because it was reported that the inhibitory effect of NDGA on 15-LOX activity was shown to be modified by methylation of the hydroxyl group of its catechol ring (Blecha et al, 2007). The inhibitory effects of CBD, CBDM, and NDGA on 5/15-LOX-catalyzed oxygenation activity were examined using purified LOX as an enzyme source.…”

“…It has been reported that 15-LOX activity is quite sensitive to the structural modifications of the catechol ring of NDGA, an isomer of resorcinol (Fig. 1A), such as methylation of its hydroxyl group (Blecha et al, 2007), although NDGA is well known as a pan-LOX inhibitor (Hope et al, 1983;Whitman et al, 2002). There have been no reports investigating whether any cannabinoid(s) including CBD "selectively and potently" inhibit the 15-LOX isoform, whereas CBD having a resorcinol ring has been shown to inhibit LOX activity (Evans et al, 1987;Russo, 2004).…”