A novel antitumor activity of deguelin targeting the insulin-like growth factor (IGF) receptor pathway via up-regulation of IGF-binding protein-3 expression in breast cancer

Abstract

In this study, we investigated the antitumor effects of deguelin in several human breast cancer cells in vitro and in vivo. Deguelin inhibited cell viability and the anchorage-dependent and anchorage-independent colony formation of triple-negative (MDA-MB-231 and MDA-MB-468) and triple-positive (MCF-7) breast cancer cells, and it significantly reduced the growth of MCF-7 cell xenograft tumors. The induction of apoptosis, inhibition of insulin-like growth factor-1 receptor (IGF-1R) signaling activation, and up-regulation of IGF-binding protein-3 (IGFBP-3) expression may be associated with deguelin-mediated antitumor effects. Our findings suggest a potential therapeutic use for deguelin in patients with triple-negative breast cancer and for those with breast cancers who are sensitive to endocrine- and HER2-targeted therapies.

Synthesis and Evaluation of a Novel Deguelin Derivative, L80, which Disrupts ATP Binding to the C-terminal Domain of Heat Shock Protein 90

“…In previous studies, we and others have demonstrated that deguelin exhibits profound antiproliferative effects on human premalignant and malignant bronchial epithelial cells and a variety of cancer cells without cytotoxicity to normal cells (Chun et al, 2003;Murillo et al, 2009;Lee et al, 2010;Thamilselvan et al, 2011;Kang et al, 2012;Mehta et al, 2013a,b;Suh et al, 2013). Furthermore, deguelin has shown in vivo effectiveness in suppressing the growth of xenograft tumors and lung tumor formation in tobacco carcinogentreated A/J mice and in genetically engineered mice with mutant K-Ras (Chun et al, 2003;Lee et al, 2005;Kim et al, 2008;Woo et al, 2009).…”

Deguelin Analogue SH-1242 Inhibits Hsp90 Activity and Exerts Potent Anticancer Efficacy with Limited Neurotoxicity

“…We and others have demonstrated that a naturally occurring rotenoid deguelin has potent anticancer activities by disrupting ATP binding to Hsp90 and thus destabilizing its client proteins, such as Akt and HIF1a (18)(19)(20)(21)(22)(23)(24). However, despite deguelin's potency, its potential Parkinsonism-like neurotoxicity may be an obstacle to further clinical development.…”

Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

“…Previous reports have shown that deguelin inhibits the survival of various cancer cells through mechanisms including DNA damage induction, reduced expression of DNA repair genes, inhibition of vasculogenic function, and blockage of anti-apoptotic pathways [13,25,26]. However, the effects of deguelin on autophagy in pancreatic cancer cells have not been previously reported.…”

“…Degulin, a retinoid extracted from Mundulea sericea (Willd), exerts pro-apoptotic activity in various cancer models including those of breast, gastric, and prostate cancer [13][14][15]. Previous studies have shown that deguelin induces apoptosis in cancer cells by targeting the AMPK and PI3K/Akt pathway [16,17].…”