A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy

Woo Young Kim, Dong Jo Chang, Bryan Hennessy, Hae Jin Kang, Jakyung Yoo, Seung Ho Han, Yoo Shin Kim, Hyun Ju Park, Seung Yong Geo, Gordon Mills, Kyu Won Kim, Waun Ki Hong, Young Ger Suh, Ho Young Lee

Research output: Contribution to journalArticle

43 Citations (Scopus)

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-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).

Original languageEnglish (US)
Pages (from-to)577-587
Number of pages11
JournalCancer Prevention Research
Volume1
Issue number7
DOIs
StatePublished - Dec 1 2008
Externally publishedYes

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Chemoprevention
Neoplasms
Non-Small Cell Lung Carcinoma
HSP90 Heat-Shock Proteins
Therapeutics
Solubility
deguelin
Hypoxia-Inducible Factor 1
Cell Line
Protein Array Analysis
1-Phosphatidylinositol 4-Kinase
Transducers
Parkinson Disease
Proteins
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Kim, W. Y., Chang, D. J., Hennessy, B., Kang, H. J., Yoo, J., Han, S. H., ... Lee, H. Y. (2008). A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy. Cancer Prevention Research, 1(7), 577-587. https://doi.org/10.1158/1940-6207.CAPR-08-0184

A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy. / Kim, Woo Young; Chang, Dong Jo; Hennessy, Bryan; Kang, Hae Jin; Yoo, Jakyung; Han, Seung Ho; Kim, Yoo Shin; Park, Hyun Ju; Geo, Seung Yong; Mills, Gordon; Kim, Kyu Won; Hong, Waun Ki; Suh, Young Ger; Lee, Ho Young.

In: Cancer Prevention Research, Vol. 1, No. 7, 01.12.2008, p. 577-587.

Research output: Contribution to journalArticle

Kim, WY, Chang, DJ, Hennessy, B, Kang, HJ, Yoo, J, Han, SH, Kim, YS, Park, HJ, Geo, SY, Mills, G, Kim, KW, Hong, WK, Suh, YG & Lee, HY 2008, 'A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy', Cancer Prevention Research, vol. 1, no. 7, pp. 577-587. https://doi.org/10.1158/1940-6207.CAPR-08-0184
Kim, Woo Young ; Chang, Dong Jo ; Hennessy, Bryan ; Kang, Hae Jin ; Yoo, Jakyung ; Han, Seung Ho ; Kim, Yoo Shin ; Park, Hyun Ju ; Geo, Seung Yong ; Mills, Gordon ; Kim, Kyu Won ; Hong, Waun Ki ; Suh, Young Ger ; Lee, Ho Young. / A novel derivative of the natural agent deguelin for cancer chemoprevention and therapy. In: Cancer Prevention Research. 2008 ; Vol. 1, No. 7. pp. 577-587.
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AU - Park, Hyun Ju

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