Statin derivatives as therapeutic agents for castration-resistant prostate cancer

Matthew A. Ingersoll, Dannah R. Miller, October Martinez, C. Brent Wakefield, Kuan Chan Hsieh, M. Vijaya Simha, Chai Lin Kao, Hui Ting Chen, Surinder Kumar Batra, Ming-Fong Lin

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Despite recent advances in modern medicine, castration-resistant prostate cancer remains an incurable disease. Subpopulations of prostate cancer cells develop castration-resistance by obtaining the complete steroidogenic ability to synthesize androgens from cholesterol. Statin derivatives, such as simvastatin, inhibit cholesterol biosynthesis and may reduce prostate cancer incidence as well as progression to advanced, metastatic phenotype. In this study, we demonstrate novel simvastatin-related molecules SVA, AM1, and AM2 suppress the tumorigenicity of prostate cancer cell lines including androgen receptor-positive LNCaP C-81 and VCaP as well as androgen receptor-negative PC-3 and DU145. This is achieved through inhibition of cell proliferation, colony formation, and migration as well as induction of S-phase cell-cycle arrest and apoptosis. While the compounds effectively block androgen receptor signaling, their mechanism of inhibition also includes suppression of the AKT pathway, in part, through disruption of the plasma membrane. SVA also possess an added effect on cell growth inhibition when combined with docetaxel. In summary, of the compounds studied, SVA is the most potent inhibitor of prostate cancer cell tumorigenicity, demonstrating its potential as a promising therapeutic agent for castration-resistant prostate cancer.

Original languageEnglish (US)
Pages (from-to)94-105
Number of pages12
JournalCancer Letters
Volume383
Issue number1
DOIs
StatePublished - Dec 1 2016

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Castration
Prostatic Neoplasms
Androgen Receptors
Simvastatin
docetaxel
Therapeutics
Cholesterol
Modern 1601-history
Cell Cycle Checkpoints
S Phase
Androgens
Cell Proliferation
Cell Membrane
Apoptosis
Phenotype
Cell Line
Incidence
Growth

Keywords

  • AKT
  • Androgen receptor
  • Cholesterol
  • ErbB-2
  • Simvastatin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ingersoll, M. A., Miller, D. R., Martinez, O., Wakefield, C. B., Hsieh, K. C., Simha, M. V., ... Lin, M-F. (2016). Statin derivatives as therapeutic agents for castration-resistant prostate cancer. Cancer Letters, 383(1), 94-105. https://doi.org/10.1016/j.canlet.2016.09.008

Statin derivatives as therapeutic agents for castration-resistant prostate cancer. / Ingersoll, Matthew A.; Miller, Dannah R.; Martinez, October; Wakefield, C. Brent; Hsieh, Kuan Chan; Simha, M. Vijaya; Kao, Chai Lin; Chen, Hui Ting; Batra, Surinder Kumar; Lin, Ming-Fong.

In: Cancer Letters, Vol. 383, No. 1, 01.12.2016, p. 94-105.

Research output: Contribution to journalArticle

Ingersoll, MA, Miller, DR, Martinez, O, Wakefield, CB, Hsieh, KC, Simha, MV, Kao, CL, Chen, HT, Batra, SK & Lin, M-F 2016, 'Statin derivatives as therapeutic agents for castration-resistant prostate cancer', Cancer Letters, vol. 383, no. 1, pp. 94-105. https://doi.org/10.1016/j.canlet.2016.09.008
Ingersoll MA, Miller DR, Martinez O, Wakefield CB, Hsieh KC, Simha MV et al. Statin derivatives as therapeutic agents for castration-resistant prostate cancer. Cancer Letters. 2016 Dec 1;383(1):94-105. https://doi.org/10.1016/j.canlet.2016.09.008
Ingersoll, Matthew A. ; Miller, Dannah R. ; Martinez, October ; Wakefield, C. Brent ; Hsieh, Kuan Chan ; Simha, M. Vijaya ; Kao, Chai Lin ; Chen, Hui Ting ; Batra, Surinder Kumar ; Lin, Ming-Fong. / Statin derivatives as therapeutic agents for castration-resistant prostate cancer. In: Cancer Letters. 2016 ; Vol. 383, No. 1. pp. 94-105.
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