A Novel Derivative of the Natural Agent Deguelin for Cancer Chemoprevention and Therapy

Abstract

The natural compound deguelin has promising preventive and therapeutic activity against diverse cancers by directly binding to heat shock protein-90 and thus suppressing its function. Potential side effects of deguelin over a certain dose, however, could be a substantial obstacle to its clinical use. To develop a derivative(s) of deguelin with reduced potential side effects, we synthesized five deguelin analogues and compared them with the parent compound and each other for structural and biochemical features; solubility; and antiproliferative effects on normal, premalignant, and malignant human bronchial epithelial (HBE) and non-small-cell lung cancer (NSCLC) cell lines. Four derivatives destabilized hypoxia-inducible factor-1α as potently as did deguelin. Reversephase protein array (RPPA) analysis in H460 NSCLC cells revealed that deguelin and the derivatives suppressed expression of a number of proteins including heat shock protein-90 clients and proteins involved in the phosphoinositide 3-kinase/Akt pathway. One derivative, SH-14, showed several features of potential superiority for clinical use: the highest apoptotic activity; no detectable influence on Src/signal transducer and activator of transcription signaling, which can promote cancer progression and is closely related to pathogenesis of Parkinson's disease (deguelin, SH-02 and SH-03 strongly activated this signaling); better aqueous solubility; and less cytotoxicity to immortalized HBE cells (versus deguelin) at a dose (1 μmol/L) that induced apoptotic activity in most premalignant and malignant HBE and NSCLC cell lines. These collective results suggest that the novel derivative SH-14 has strong potential for cancer chemoprevention and therapy, with equivalent efficacy and lesser toxicity (versus deguelin).Cancer remains one of the leading causes of death worldwide despite several decades of intensive efforts to prevent and treat it. Most effective cancer therapy agents are toxic in normal tissue, indicating the need for novel preventive and therapeutic drugs with no or low toxicity. Deguelin, a rotenoid isolated from the African plant Mundulea sericea (Leguminosae) and other plants (1), is a heat shock protein-90 (Hsp90) inhibitor with potent apoptotic and antiangiogenic effects on transformed cells and a variety of cancer cells but without cytotoxicity in normal cells (2, 3), making it a promising cancer prevention and therapy agent. We recently showed that deguelin has promising activity against a number of human cancers, at least in part, because it binds to the ATP pocket of Hsp90α, which leads to decreased expression of a number of Hsp90 client proteins, including mutated p53, cyclin-dependent kinase 4, mitogen-activated protein kinase kinase-1/2, Akt, and hypoxia-inducible factor (HIF)-1α, in addition to decreased expression of previously known deguelin targets such as cyclooxygenase-2, necrosis factor κB, and nucleoporin 98 kDa (Nup98).Hsp90 facilitates the adaptation of cancer cells to many environmental stresses owing to its functi...

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

“…However, the potential neuronal toxicity of deguelin, which most likely occurs through the inhibition of NADH dehydrogenase (Caboni et al, 2004), raises concern for its use in human cancer patients. Hence, we attempted to develop deguelin derivatives as lead compounds for the development of novel Hsp90 inhibitors (Oh et al, 2007;Kim et al, 2008;Chang et al, 2012). In our structure-activity relationship studies, the 2,2-dimethyl-2H-chromene moiety of deguelin seemed to be responsible for occupying the ATP-binding pocket of Hsp90 via hydrophobic interactions.…”

“…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). Structural biology and molecular modeling techniques have revealed that deguelin exhibits antitumor and antiangiogenic activities by targeting heat shock protein 90 (Hsp90), which functions as a molecular chaperone and is required for the stability and proper function of many oncogenic proteins, including hypoxia inducible factor (HIF)-1a; mutated p53, mitogen-activated protein kinase kinase (MEK1/2); cyclin-dependent kinase 4; erbB2; and Akt (Oh et al, 2007(Oh et al, , 2008.…”

Deguelin promotes apoptosis and inhibits angiogenesis of gastric cancer

“…HIF-1· is a new target for the antiangiogenic therapy of gastric cancer. Deguelin has been reported to be an anti-angiogenic agent that targets HIF-1· in lung cancer (31)(32)(33)(34)(35). Earlier studies showed that the PI3K/ Akt/mTOR pathway regulates HIF-1· protein translation through mTOR (36,37).…”

“…Deguelin has been reported to be an anti-angiogenic drug that targets HIF-1· in lung cancer (31)(32)(33)(34)(35). To determine the effect of deguelin on expression of angiogenic factors in gastric cancer cells, VEGF and HIF-1· expression were investigated by RT-PCR.…”

Cancer Prevention Research: Back to the Future

“…CaPR published possibly the first study of angiogenesis targeting in genetically engineered mouse lung carcinogenesis (41), assessing sunitinib (thought to primarily affect the vascular endothelial growth factor receptor [VEGFR]), and published a study of CD36 targeting in chemically induced oral carcinogenesis (42). Four other CaPR papers report targeting in the angiogenesis-related phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway (43)-AKT inhibition with the natural agent myoinositol in human bronchial dysplasia (44), which built on earlier work by this group and others in targeting mTOR in genetically engineered mouse lungs (45,46); mTOR inhibition for preventing chemically induced mouse oral carcinogenesis (47); and in vitro and animal model targeting in this pathway with analogues of the natural agent deguelin (48,49). As highlighted by these papers and a CaPR perspective article (50), targeting angiogenesis and the microenvironment are an exciting new frontier of cancer chemoprevention.…”