title: 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 (SH-02, SH-03, SH-09, SH-14, and SH-15) 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-1alpha as potently as did deguelin. Reverse-phase 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 micromol/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).
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Woo-Young
authors.initials: WY
authors.lastname: Kim
authors.forename: Dong Jo
authors.initials: DJ
authors.lastname: Chang
authors.forename: Bryan
authors.initials: B
authors.lastname: Hennessy
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kang
authors.forename: Jakyung
authors.initials: J
authors.lastname: Yoo
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Han
authors.forename: Yoo-Shin
authors.initials: YS
authors.lastname: Kim
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Park
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Seo
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Geo
authors.forename: Gordon
authors.initials: G
authors.lastname: Mills
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D018890:Chemoprevention / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012402:Rotenone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C569212:9,10-dimethoxy-3,3-dimethyl-7,7a,13,13atetrahydro-3H-chromeno(3,4-b)pyrano(2,3-h)chromen-7-ol; D000970:Antineoplastic Agents; D012402:Rotenone; C107676:deguelin