Luteinizing hormone-releasing hormone (LHRH)-I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo

Jianguo Wen, Yongdong Feng, Chad C. Bjorklund, Michael Wang, Robert Z. Orlowski, Zheng Zheng Shi, Bing Liao, Jacqueline O'Hare, Youli Zu, Andrew V. Schally, Chung Che Chang

Research output: Contribution to journalArticle

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Abstract

The objective of this study was to determine the effects of an luteinizing hormone-releasing hormone (LHRH)-I antagonist, Cetrorelix, on human multiple myeloma (MM) cells and to elucidate the mechanisms of action. We showed that LHRH-I and LHRHR-I genes were expressed in MM cell lines and primary MM cells. Treatment with Cetrorelix inhibited growth and colony-forming ability of myeloma cells, including cell lines resistant to arsenic trioxide, bortezomib, or lenalidomide. Cetrorelix induced apoptosis in myeloma cells including primary myeloma cells. In addition, Cetrorelix inhibited the growth of human myeloma cells xenografted into mice without any apparent side effects. Cetrorelix downregulated the nuclear factor-kappa B (NF-κB) pathway activity and the expression of cytokines, including interleukin 6, insulin-like growth factor 1, VEGF-A, and stromal-derived factor 1, important for myeloma cell growth and survival in myeloma cells and/or marrow stromal cells from myeloma patients. Cetrorelix decreased the phosphorylation of extra-cellular signal regulated kinase 1/2 and STAT3 in myeloma cells, two crucial pathways for myeloma cells growth and survival. Moreover, the expression of p21 and p53 was increased, whereas that of antiapoptotic proteins Bcl-2 and Bcl-xL was reduced by Cetrorelix. Our findings indicate that Cetrorelix induces cytotoxicity in myeloma cells through various mechanisms and provide a rationale for investigating Cetrorelix for the treatment of MM.

Original languageEnglish (US)
Pages (from-to)148-158
Number of pages11
JournalMolecular Cancer Therapeutics
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

Fingerprint

Hormone Antagonists
Gonadotropin-Releasing Hormone
Growth
Multiple Myeloma
Cell Survival
cetrorelix
In Vitro Techniques
Cell Line
NF-kappa B
Somatomedins
Stromal Cells
Vascular Endothelial Growth Factor A
Interleukin-6
Phosphotransferases
Down-Regulation
Bone Marrow
Phosphorylation
Apoptosis
Cytokines

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Luteinizing hormone-releasing hormone (LHRH)-I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo. / Wen, Jianguo; Feng, Yongdong; Bjorklund, Chad C.; Wang, Michael; Orlowski, Robert Z.; Shi, Zheng Zheng; Liao, Bing; O'Hare, Jacqueline; Zu, Youli; Schally, Andrew V.; Chang, Chung Che.

In: Molecular Cancer Therapeutics, Vol. 10, No. 1, 01.01.2011, p. 148-158.

Research output: Contribution to journalArticle

Wen, J, Feng, Y, Bjorklund, CC, Wang, M, Orlowski, RZ, Shi, ZZ, Liao, B, O'Hare, J, Zu, Y, Schally, AV & Chang, CC 2011, 'Luteinizing hormone-releasing hormone (LHRH)-I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo', Molecular Cancer Therapeutics, vol. 10, no. 1, pp. 148-158. https://doi.org/10.1158/1535-7163.MCT-10-0829
Wen, Jianguo ; Feng, Yongdong ; Bjorklund, Chad C. ; Wang, Michael ; Orlowski, Robert Z. ; Shi, Zheng Zheng ; Liao, Bing ; O'Hare, Jacqueline ; Zu, Youli ; Schally, Andrew V. ; Chang, Chung Che. / Luteinizing hormone-releasing hormone (LHRH)-I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo. In: Molecular Cancer Therapeutics. 2011 ; Vol. 10, No. 1. pp. 148-158.
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abstract = "The objective of this study was to determine the effects of an luteinizing hormone-releasing hormone (LHRH)-I antagonist, Cetrorelix, on human multiple myeloma (MM) cells and to elucidate the mechanisms of action. We showed that LHRH-I and LHRHR-I genes were expressed in MM cell lines and primary MM cells. Treatment with Cetrorelix inhibited growth and colony-forming ability of myeloma cells, including cell lines resistant to arsenic trioxide, bortezomib, or lenalidomide. Cetrorelix induced apoptosis in myeloma cells including primary myeloma cells. In addition, Cetrorelix inhibited the growth of human myeloma cells xenografted into mice without any apparent side effects. Cetrorelix downregulated the nuclear factor-kappa B (NF-κB) pathway activity and the expression of cytokines, including interleukin 6, insulin-like growth factor 1, VEGF-A, and stromal-derived factor 1, important for myeloma cell growth and survival in myeloma cells and/or marrow stromal cells from myeloma patients. Cetrorelix decreased the phosphorylation of extra-cellular signal regulated kinase 1/2 and STAT3 in myeloma cells, two crucial pathways for myeloma cells growth and survival. Moreover, the expression of p21 and p53 was increased, whereas that of antiapoptotic proteins Bcl-2 and Bcl-xL was reduced by Cetrorelix. Our findings indicate that Cetrorelix induces cytotoxicity in myeloma cells through various mechanisms and provide a rationale for investigating Cetrorelix for the treatment of MM.",
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AU - Orlowski, Robert Z.

AU - Shi, Zheng Zheng

AU - Liao, Bing

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AU - Schally, Andrew V.

AU - Chang, Chung Che

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