Prevention and treatment of experimental estrogen receptor- negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl ester and the rexinoid LG100268

Karen Liby, Renee Risingsong, Darlene B. Royce, Charlotte R. Williams, Mark M. Yore, Tadashi Honda, Gordon W. Gribble, William W. Lamph, Nicola Vannini, Ilaria Sogno, Adriana Albini, Michael B. Sporn

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Abstract

Purpose: To test whether the triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)- dien-28-oic acid methyl ester (CDDO-Me) and the rexinoid LG100268 (268) prevent the formation of estrogen receptor (ER)-negative mammary tumors or either arrest the growth or cause regression of established tumors in MMTV-neu mice. Experimental Design: For prevention, mice were fed control diet, CDDO-Me (60 mg/kg diet), 268 (20 mg/kg diet), or the combination for 45 weeks. For treatment, mice with established tumors at least 4 mm in diameter were fed control diet, CDDO-Me (100 mg/kg diet), 268 (60 mg/kg diet), or the combination for 4 weeks. Results: CDDO-Me and 268 significantly delayed the development of ER-negative tumors, with a 14- and 24-week delay, respectively, compared with the control group for the time required to reach 50% tumor incidence. The combination of CDDO-Me and 268 was significantly more potent than the individual drugs, as only one tumor was found in the combination group, after 45 weeks on diet, at which time all control animals had tumors. Treating established tumors with CDDO-Me arrested the growth of 86% of the tumors, and 268 induced tumor regression in 85% of tumors. CDDO-Me and 268 target different signaling pathways and cell types. CDDO-Me inhibited constitutive STAT3 phosphorylation and the degradation of IKBα in ER-negative breast cancer cells, whereas 268 blocked IKBα degradation and the release of interleukin-6 in RAW264.7 macrophage-like cells, inhibited the ability of endothelial cells to organize into networks, and blocked angiogenesis in vivo. Conclusions: CDDO-Me and 268 are useful as individual drugs to prevent ER-negative mammary tumorigenesis and to treat established tumors. They synergize when used in combination for prevention.

Original languageEnglish
Pages (from-to)4556-4563
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number14
DOIs
Publication statusPublished - Jul 15 2008

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Estrogen Receptors
Carcinogenesis
Breast
Diet
Neoplasms
LG 100268
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Breast Neoplasms
Growth
Pharmaceutical Preparations
Interleukin-6
Esters
Research Design
Endothelial Cells
Macrophages
Phosphorylation
Control Groups
Acids
Incidence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Prevention and treatment of experimental estrogen receptor- negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl ester and the rexinoid LG100268. / Liby, Karen; Risingsong, Renee; Royce, Darlene B.; R. Williams, Charlotte; Yore, Mark M.; Honda, Tadashi; Gribble, Gordon W.; Lamph, William W.; Vannini, Nicola; Sogno, Ilaria; Albini, Adriana; Sporn, Michael B.

In: Clinical Cancer Research, Vol. 14, No. 14, 15.07.2008, p. 4556-4563.

Research output: Contribution to journalArticle

Liby, K, Risingsong, R, Royce, DB, R. Williams, C, Yore, MM, Honda, T, Gribble, GW, Lamph, WW, Vannini, N, Sogno, I, Albini, A & Sporn, MB 2008, 'Prevention and treatment of experimental estrogen receptor- negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl ester and the rexinoid LG100268', Clinical Cancer Research, vol. 14, no. 14, pp. 4556-4563. https://doi.org/10.1158/1078-0432.CCR-08-0040
Liby, Karen ; Risingsong, Renee ; Royce, Darlene B. ; R. Williams, Charlotte ; Yore, Mark M. ; Honda, Tadashi ; Gribble, Gordon W. ; Lamph, William W. ; Vannini, Nicola ; Sogno, Ilaria ; Albini, Adriana ; Sporn, Michael B. / Prevention and treatment of experimental estrogen receptor- negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl ester and the rexinoid LG100268. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 14. pp. 4556-4563.
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abstract = "Purpose: To test whether the triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)- dien-28-oic acid methyl ester (CDDO-Me) and the rexinoid LG100268 (268) prevent the formation of estrogen receptor (ER)-negative mammary tumors or either arrest the growth or cause regression of established tumors in MMTV-neu mice. Experimental Design: For prevention, mice were fed control diet, CDDO-Me (60 mg/kg diet), 268 (20 mg/kg diet), or the combination for 45 weeks. For treatment, mice with established tumors at least 4 mm in diameter were fed control diet, CDDO-Me (100 mg/kg diet), 268 (60 mg/kg diet), or the combination for 4 weeks. Results: CDDO-Me and 268 significantly delayed the development of ER-negative tumors, with a 14- and 24-week delay, respectively, compared with the control group for the time required to reach 50{\%} tumor incidence. The combination of CDDO-Me and 268 was significantly more potent than the individual drugs, as only one tumor was found in the combination group, after 45 weeks on diet, at which time all control animals had tumors. Treating established tumors with CDDO-Me arrested the growth of 86{\%} of the tumors, and 268 induced tumor regression in 85{\%} of tumors. CDDO-Me and 268 target different signaling pathways and cell types. CDDO-Me inhibited constitutive STAT3 phosphorylation and the degradation of IKBα in ER-negative breast cancer cells, whereas 268 blocked IKBα degradation and the release of interleukin-6 in RAW264.7 macrophage-like cells, inhibited the ability of endothelial cells to organize into networks, and blocked angiogenesis in vivo. Conclusions: CDDO-Me and 268 are useful as individual drugs to prevent ER-negative mammary tumorigenesis and to treat established tumors. They synergize when used in combination for prevention.",
author = "Karen Liby and Renee Risingsong and Royce, {Darlene B.} and {R. Williams}, Charlotte and Yore, {Mark M.} and Tadashi Honda and Gribble, {Gordon W.} and Lamph, {William W.} and Nicola Vannini and Ilaria Sogno and Adriana Albini and Sporn, {Michael B.}",
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T1 - Prevention and treatment of experimental estrogen receptor- negative mammary carcinogenesis by the synthetic triterpenoid CDDO-methyl ester and the rexinoid LG100268

AU - Liby, Karen

AU - Risingsong, Renee

AU - Royce, Darlene B.

AU - R. Williams, Charlotte

AU - Yore, Mark M.

AU - Honda, Tadashi

AU - Gribble, Gordon W.

AU - Lamph, William W.

AU - Vannini, Nicola

AU - Sogno, Ilaria

AU - Albini, Adriana

AU - Sporn, Michael B.

PY - 2008/7/15

Y1 - 2008/7/15

N2 - Purpose: To test whether the triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)- dien-28-oic acid methyl ester (CDDO-Me) and the rexinoid LG100268 (268) prevent the formation of estrogen receptor (ER)-negative mammary tumors or either arrest the growth or cause regression of established tumors in MMTV-neu mice. Experimental Design: For prevention, mice were fed control diet, CDDO-Me (60 mg/kg diet), 268 (20 mg/kg diet), or the combination for 45 weeks. For treatment, mice with established tumors at least 4 mm in diameter were fed control diet, CDDO-Me (100 mg/kg diet), 268 (60 mg/kg diet), or the combination for 4 weeks. Results: CDDO-Me and 268 significantly delayed the development of ER-negative tumors, with a 14- and 24-week delay, respectively, compared with the control group for the time required to reach 50% tumor incidence. The combination of CDDO-Me and 268 was significantly more potent than the individual drugs, as only one tumor was found in the combination group, after 45 weeks on diet, at which time all control animals had tumors. Treating established tumors with CDDO-Me arrested the growth of 86% of the tumors, and 268 induced tumor regression in 85% of tumors. CDDO-Me and 268 target different signaling pathways and cell types. CDDO-Me inhibited constitutive STAT3 phosphorylation and the degradation of IKBα in ER-negative breast cancer cells, whereas 268 blocked IKBα degradation and the release of interleukin-6 in RAW264.7 macrophage-like cells, inhibited the ability of endothelial cells to organize into networks, and blocked angiogenesis in vivo. Conclusions: CDDO-Me and 268 are useful as individual drugs to prevent ER-negative mammary tumorigenesis and to treat established tumors. They synergize when used in combination for prevention.

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