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

Authors' Affiliations: Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² System Biology, and ³ Gynecologic Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁴ College of Pharmacy, Seoul National University, Seoul, Korea; ⁵ College of Pharmacy, Sungkyunkwan University, Suwon, Korea; and ⁶ College of Pharmacy, Woosuk University, Samrye, Korea

Requests for reprints: Ho-Young Lee, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. Phone: 713-745-0769; Fax: 713-792-0430; E-mail: hlee{at}mdanderson.org or Young-Ger Suh, College of Pharmacy, Seoul National University, ShinLim Dong, Kwanak Ku, Seoul, 151-742, Korea. E-mail: ygsuh{at}snu.ac.kr.

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-1 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 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).

Key Words: Reverse phase protein array • Hsp90 • HIF-1 • deguelin • lung cancer

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