Prevention of prostate cancer with oleanane synthetic triterpenoid CDDO-Me in the TRAMP mouse model of prostate cancer

Xiaohua Gao, Dorrah Deeb, Yongbo Liu, Ali Syed Arbab, George W. Divine, Scott A. Dulchavsky, Subhash C. Gautam

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), a synthetic analog of oleanolic acid, and its C28 methyl ester derivative (CDDO-Me), have shown potent antitumorigenic activity against a wide range of cancer cell lines, including prostate cancer cells in vitro, and inhibited the development of liver and lung cancer in vivo. In the present study, we examined the efficacy of CDDO-Me in preventing the development and progression of prostate cancer in the transgenic adenocarinoma of the mouse prostate (TRAMP) model. CDDO-Me inhibited the growth of murine TRAMPC-1 prostate cancer cells by inducing apoptosis through the inhibition of antiapoptotic p-Akt, p-mTOR and NF-κB. Early intervention with CDDO-Me (7.5 mg/kg) initiated at five weeks of age for 20 wk inhibited the progression of the preneoplastic lesions (low-grade PIN and high-grade-PIN) to adenocarcinoma in the dorsolateral prostate (DLP) and ventral prostate (VP) lobes of TRAMP mice. Even delayed administration of CDDO-Me started at 12 wk of age for 12 wk inhibited the development of adenocarcimona of the prostate. Both early and late treatment with CDDO-Me inhibited the metastasis of tumor to the distant organs. Treatment withCDDO-Me inhibited the expression of prosurvival p-Akt and NF-κB in the prostate and knocking-down Akt in TRAMPC-1 tumor cells sensitized them to CDDO-Me. These findings indicated that Akt is a target for apoptoxicity in TRAMPC-1 cells in vitro and potentially a target of CDDO-Me for inhibition of prostate cancer in vivo.

Original languageEnglish (US)
Pages (from-to)3353-3369
Number of pages17
JournalCancers
Volume3
Issue number3
DOIs
StatePublished - Sep 1 2011

Fingerprint

Transgenic Mice
Prostate
Prostatic Neoplasms
Oleanolic Acid
Neoplasms
Liver Neoplasms
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
oleanane
Lung Neoplasms
Esters
Adenocarcinoma
Apoptosis
Neoplasm Metastasis
Cell Line
Growth

Keywords

  • Akt/mTOR/NF-kB signaling
  • Apoptosis
  • CDDO-Me
  • Chemoprevention
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Prevention of prostate cancer with oleanane synthetic triterpenoid CDDO-Me in the TRAMP mouse model of prostate cancer. / Gao, Xiaohua; Deeb, Dorrah; Liu, Yongbo; Arbab, Ali Syed; Divine, George W.; Dulchavsky, Scott A.; Gautam, Subhash C.

In: Cancers, Vol. 3, No. 3, 01.09.2011, p. 3353-3369.

Research output: Contribution to journalArticle

Gao, Xiaohua ; Deeb, Dorrah ; Liu, Yongbo ; Arbab, Ali Syed ; Divine, George W. ; Dulchavsky, Scott A. ; Gautam, Subhash C. / Prevention of prostate cancer with oleanane synthetic triterpenoid CDDO-Me in the TRAMP mouse model of prostate cancer. In: Cancers. 2011 ; Vol. 3, No. 3. pp. 3353-3369.
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AU - Dulchavsky, Scott A.

AU - Gautam, Subhash C.

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AB - 2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), a synthetic analog of oleanolic acid, and its C28 methyl ester derivative (CDDO-Me), have shown potent antitumorigenic activity against a wide range of cancer cell lines, including prostate cancer cells in vitro, and inhibited the development of liver and lung cancer in vivo. In the present study, we examined the efficacy of CDDO-Me in preventing the development and progression of prostate cancer in the transgenic adenocarinoma of the mouse prostate (TRAMP) model. CDDO-Me inhibited the growth of murine TRAMPC-1 prostate cancer cells by inducing apoptosis through the inhibition of antiapoptotic p-Akt, p-mTOR and NF-κB. Early intervention with CDDO-Me (7.5 mg/kg) initiated at five weeks of age for 20 wk inhibited the progression of the preneoplastic lesions (low-grade PIN and high-grade-PIN) to adenocarcinoma in the dorsolateral prostate (DLP) and ventral prostate (VP) lobes of TRAMP mice. Even delayed administration of CDDO-Me started at 12 wk of age for 12 wk inhibited the development of adenocarcimona of the prostate. Both early and late treatment with CDDO-Me inhibited the metastasis of tumor to the distant organs. Treatment withCDDO-Me inhibited the expression of prosurvival p-Akt and NF-κB in the prostate and knocking-down Akt in TRAMPC-1 tumor cells sensitized them to CDDO-Me. These findings indicated that Akt is a target for apoptoxicity in TRAMPC-1 cells in vitro and potentially a target of CDDO-Me for inhibition of prostate cancer in vivo.

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