Induction of apoptosis by AN-152, a cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), in LHRH-R positive human breast cancer cells is independent of multidrug resistance-1 (MDR-1) system

Andreas R. Günthert, Carsten Gründker, Till Bongertz, Attila Nagy, Andrew V Schally, Günter Emons

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Objective. More than 50% of human breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH-R). These receptors can be used for targeted chemotherapy with agents like AN-152, in which doxorubicin is linked to analog [D-Lys 6]LHRH. We compared the effects of AN-152 and doxorubicin in human breast cancer cells. Methods. MCF-7, T47D, HCC-70 and ZR-75-1 cells were analysed for expression of LHRH-R using RT-PCR, immunostaining and flow cytometry. Apoptosis and expression of MDR-1 gene product Pgp were measured by flow cytometry. Cleavage of doxorubicin from AN-152 by serum carboxylesterase (CE) was inhibited by DFP. Results. In MCF-7, T47D and HCC-70 cells we found cell surface expression of LHRH-R. In ZR-75-1 cells only sparse surface expression was found. In HCC-70 cells, induction of apoptosis by AN-152 was stronger than by doxorubicin in medium containing fetal calf serum (FCS). Pretreatment with DFP increased AN-152-induced apoptosis in LHRH-R positive MCF-7 and HCC-70 cells and reduced apoptosis in ZR-75-1 cells. In serum-free medium apoptosis induced by AN-152 was stronger than that induced by doxorubicin in HCC-70, T47D and MCF-7 cells, but weaker in ZR-75-1 cells. In medium containing FCS, both AN-152 and doxorubicin induced surface expression of MDR-1 gene product Pgp, but the effect of AN-152 was weaker. Pgp-expression induced by AN-152 was inhibited by pretreatment with DFP. AN-152 did not induce Pgp-expression in serum-free medium. Conclusion.The cytotoxic LHRH analog AN-152 induces apoptosis independent of MDR-1 in LHRH-R positive breast cancer cells. The efficacy and/or specificity of AN-152 is improved by suppression or absence of CE activity.

Original languageEnglish
Pages (from-to)255-264
Number of pages10
JournalBreast Cancer Research and Treatment
Volume87
Issue number3
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

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Multiple Drug Resistance
Gonadotropin-Releasing Hormone
Apoptosis
Breast Neoplasms
Doxorubicin
Isoflurophate
MDR Genes
Carboxylesterase
Serum-Free Culture Media
lysine(6)-doxorubicin LHRH
Flow Cytometry
Serum
LHRH Receptors
MCF-7 Cells

Keywords

  • AN-152
  • apoptosis
  • breast cancer
  • MDR-1
  • P-glycoprotein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Induction of apoptosis by AN-152, a cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), in LHRH-R positive human breast cancer cells is independent of multidrug resistance-1 (MDR-1) system. / Günthert, Andreas R.; Gründker, Carsten; Bongertz, Till; Nagy, Attila; Schally, Andrew V; Emons, Günter.

In: Breast Cancer Research and Treatment, Vol. 87, No. 3, 01.10.2004, p. 255-264.

Research output: Contribution to journalArticle

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title = "Induction of apoptosis by AN-152, a cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), in LHRH-R positive human breast cancer cells is independent of multidrug resistance-1 (MDR-1) system",
abstract = "Objective. More than 50{\%} of human breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH-R). These receptors can be used for targeted chemotherapy with agents like AN-152, in which doxorubicin is linked to analog [D-Lys 6]LHRH. We compared the effects of AN-152 and doxorubicin in human breast cancer cells. Methods. MCF-7, T47D, HCC-70 and ZR-75-1 cells were analysed for expression of LHRH-R using RT-PCR, immunostaining and flow cytometry. Apoptosis and expression of MDR-1 gene product Pgp were measured by flow cytometry. Cleavage of doxorubicin from AN-152 by serum carboxylesterase (CE) was inhibited by DFP. Results. In MCF-7, T47D and HCC-70 cells we found cell surface expression of LHRH-R. In ZR-75-1 cells only sparse surface expression was found. In HCC-70 cells, induction of apoptosis by AN-152 was stronger than by doxorubicin in medium containing fetal calf serum (FCS). Pretreatment with DFP increased AN-152-induced apoptosis in LHRH-R positive MCF-7 and HCC-70 cells and reduced apoptosis in ZR-75-1 cells. In serum-free medium apoptosis induced by AN-152 was stronger than that induced by doxorubicin in HCC-70, T47D and MCF-7 cells, but weaker in ZR-75-1 cells. In medium containing FCS, both AN-152 and doxorubicin induced surface expression of MDR-1 gene product Pgp, but the effect of AN-152 was weaker. Pgp-expression induced by AN-152 was inhibited by pretreatment with DFP. AN-152 did not induce Pgp-expression in serum-free medium. Conclusion.The cytotoxic LHRH analog AN-152 induces apoptosis independent of MDR-1 in LHRH-R positive breast cancer cells. The efficacy and/or specificity of AN-152 is improved by suppression or absence of CE activity.",
keywords = "AN-152, apoptosis, breast cancer, MDR-1, P-glycoprotein",
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T1 - Induction of apoptosis by AN-152, a cytotoxic analog of luteinizing hormone-releasing hormone (LHRH), in LHRH-R positive human breast cancer cells is independent of multidrug resistance-1 (MDR-1) system

AU - Günthert, Andreas R.

AU - Gründker, Carsten

AU - Bongertz, Till

AU - Nagy, Attila

AU - Schally, Andrew V

AU - Emons, Günter

PY - 2004/10/1

Y1 - 2004/10/1

N2 - Objective. More than 50% of human breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH-R). These receptors can be used for targeted chemotherapy with agents like AN-152, in which doxorubicin is linked to analog [D-Lys 6]LHRH. We compared the effects of AN-152 and doxorubicin in human breast cancer cells. Methods. MCF-7, T47D, HCC-70 and ZR-75-1 cells were analysed for expression of LHRH-R using RT-PCR, immunostaining and flow cytometry. Apoptosis and expression of MDR-1 gene product Pgp were measured by flow cytometry. Cleavage of doxorubicin from AN-152 by serum carboxylesterase (CE) was inhibited by DFP. Results. In MCF-7, T47D and HCC-70 cells we found cell surface expression of LHRH-R. In ZR-75-1 cells only sparse surface expression was found. In HCC-70 cells, induction of apoptosis by AN-152 was stronger than by doxorubicin in medium containing fetal calf serum (FCS). Pretreatment with DFP increased AN-152-induced apoptosis in LHRH-R positive MCF-7 and HCC-70 cells and reduced apoptosis in ZR-75-1 cells. In serum-free medium apoptosis induced by AN-152 was stronger than that induced by doxorubicin in HCC-70, T47D and MCF-7 cells, but weaker in ZR-75-1 cells. In medium containing FCS, both AN-152 and doxorubicin induced surface expression of MDR-1 gene product Pgp, but the effect of AN-152 was weaker. Pgp-expression induced by AN-152 was inhibited by pretreatment with DFP. AN-152 did not induce Pgp-expression in serum-free medium. Conclusion.The cytotoxic LHRH analog AN-152 induces apoptosis independent of MDR-1 in LHRH-R positive breast cancer cells. The efficacy and/or specificity of AN-152 is improved by suppression or absence of CE activity.

AB - Objective. More than 50% of human breast cancers express receptors for luteinizing hormone-releasing hormone (LHRH-R). These receptors can be used for targeted chemotherapy with agents like AN-152, in which doxorubicin is linked to analog [D-Lys 6]LHRH. We compared the effects of AN-152 and doxorubicin in human breast cancer cells. Methods. MCF-7, T47D, HCC-70 and ZR-75-1 cells were analysed for expression of LHRH-R using RT-PCR, immunostaining and flow cytometry. Apoptosis and expression of MDR-1 gene product Pgp were measured by flow cytometry. Cleavage of doxorubicin from AN-152 by serum carboxylesterase (CE) was inhibited by DFP. Results. In MCF-7, T47D and HCC-70 cells we found cell surface expression of LHRH-R. In ZR-75-1 cells only sparse surface expression was found. In HCC-70 cells, induction of apoptosis by AN-152 was stronger than by doxorubicin in medium containing fetal calf serum (FCS). Pretreatment with DFP increased AN-152-induced apoptosis in LHRH-R positive MCF-7 and HCC-70 cells and reduced apoptosis in ZR-75-1 cells. In serum-free medium apoptosis induced by AN-152 was stronger than that induced by doxorubicin in HCC-70, T47D and MCF-7 cells, but weaker in ZR-75-1 cells. In medium containing FCS, both AN-152 and doxorubicin induced surface expression of MDR-1 gene product Pgp, but the effect of AN-152 was weaker. Pgp-expression induced by AN-152 was inhibited by pretreatment with DFP. AN-152 did not induce Pgp-expression in serum-free medium. Conclusion.The cytotoxic LHRH analog AN-152 induces apoptosis independent of MDR-1 in LHRH-R positive breast cancer cells. The efficacy and/or specificity of AN-152 is improved by suppression or absence of CE activity.

KW - AN-152

KW - apoptosis

KW - breast cancer

KW - MDR-1

KW - P-glycoprotein

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