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 |
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Authors: | Andreas R Gumlnthert Carsten Grumlndker Till Bongertz Attila Nagy Andrew V Schally Gumlnter Emons |
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Institution: | (1) Department of Gynecology and Obstetrics, Robert-Koch-Street 40, Germany;(2) Tulane University Medical Center and Veterans Affairs Medical Center, LA, USA |
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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-Lys6]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. |
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Keywords: | AN-152 apoptosis breast cancer MDR-1 P-glycoprotein |
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