Internalization of cytotoxic analog AN-152 of luteinizing hormone-releasing hormone induces apoptosis in human endometrial and ovarian cancer cell lines independent of multidrug resistance-1 (MDR-1) system

Autor: Andrew V. Schally, Andreas R. Günthert, Thilo Schlott, Günter Emons, Till Bongertz, Attila Nagy, Carsten Gründker
Rok vydání: 2004
Předmět:
endocrine system
medicine.medical_specialty
Programmed cell death
Apoptosis
Flow cytometry
Gonadotropin-Releasing Hormone
03 medical and health sciences
0302 clinical medicine
Internal medicine
Tumor Cells
Cultured
medicine
Humans
Cytotoxic T cell
Doxorubicin
Receptor
030304 developmental biology
Ovarian Neoplasms
0303 health sciences
Antibiotics
Antineoplastic
Microscopy
Confocal
Dose-Response Relationship
Drug
medicine.diagnostic_test
business.industry
Obstetrics and Gynecology
Receptors
LH
medicine.disease
female genital diseases and pregnancy complications
Endometrial Neoplasms
3. Good health
Gene Expression Regulation
Neoplastic
Phosphoric Triester Hydrolases
Endocrinology
Cell culture
030220 oncology & carcinogenesis
Cancer research
Female
Genes
MDR
business
Ovarian cancer
medicine.drug
Zdroj: American Journal of Obstetrics and Gynecology. 191:1164-1172
ISSN: 0002-9378
Popis: Objective Eighty percent of human ovarian and endometrial cancers express receptors for luteinizing hormone–releasing hormone (LHRH-R). These receptors can be used for targeted chemotherapy with agents such as AN-152, in which doxorubicin is linked to analog [D-Lys 6 ]-LHRH. Direct receptor-mediated antiproliferative effects of AN-152 have been shown in vitro and in vivo. In LHRH-R positive cell lines, AN-152 was more effective than doxorubicin at equimolar concentrations. This study was designed to investigate the mechanism of action of AN-512 in ovarian and endometrial cancer cells in vitro. Study design Three ovarian (SKOV-3, NIH:OVCAR-3, EFO-21) and 2 endometrial carcinoma cell lines (Ishikawa, HEC-1A) were evaluated for doxorubicin- or AN-152–induced apoptosis. Internalization and cytoplasmic release of AN-152 was monitored by confocal laser scanning microscopy and inhibited by chloroquine. Cleavage of doxorubicin from AN-152 was inhibited by carboxylesterase inhibitor, diisopropyl fluorophosphate (DFP). The surface expression of multidrug resistance-1 (MDR-1) gene product P-glycoprotein (Pgp) was measured by flow cytometry. Results Induction of apoptosis by AN-152 in LHRH-R positive Ishikawa, HEC-1A, EFO-21, and NIH:OVCAR-3 cells was significantly higher than that induced by doxorubicin, whereas the percentage of apoptotic cells in LHRH-R negative SKOV-3 was higher after treatment with doxorubicin. In EFO-21 cells, apoptosis induced by AN-152 was inhibited by pretreatment with chloroquine. Pretreatment with DFP increased AN-152–induced apoptosis in LHRH-R positive cells and reduced apoptosis in LHRH-R negative SKOV-3. Both AN-152 and doxorubicin induced surface expression of MDR-1 gene product Pgp, but the effect of AN-152 was smaller than that of doxorubicin. Pgp surface expression induced by AN-152 was inhibited by pretreatment with DFP. Conclusion AN-152 is internalized through the LHRH-R and induces apoptosis in LHRH-R–positive human ovarian and endometrial cancer cell lines without activating the MDR-1 efflux pump system. The efficacy and specificity of AN-152 is inversely correlated with carboxylesterase activity.
Databáze: OpenAIRE
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