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

doi:10.1007/s10549-004-8806-8

Cited by 26 publications

(20 citation statements)

References 27 publications

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“…AN-201 caused an increase of the mRNA levels for the MDR-1 in OV-1063 ovarian cancer and an induction of MDR-1, MRP-1, and BCRP in ES-2 ovarian cancer. Similar results were observed in vitro in the HEC-1A endometrial cancer line after treatment with the targeted cytotoxic LHRH analog AN-152 (23). Both AN-152 and its radical DOX induced surface expression of MDR-1 gene product P-glycoprotein, but the effect of AN-152 was smaller than that of DOX.…”

Section: Discussionsupporting

confidence: 79%

Therapy of ovarian cancers with targeted cytotoxic analogs of bombesin, somatostatin, and luteinizing hormone-releasing hormone and their combinations

Buchholz

Keller

Schally

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionsupporting

confidence: 79%

Therapy of ovarian cancers with targeted cytotoxic analogs of bombesin, somatostatin, and luteinizing hormone-releasing hormone and their combinations

Buchholz

Keller

Schally

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, we could demonstrate that AEZS-108 (AN-152)-induced apoptosis in human endometrial, ovarian and breast cancer cell lines is independent of the multidrug resistance-1 (MDR-1) system (11,12). Because of the LHRH receptor-mediated entry of AEZS-108 (AN-152) into the cancer cells, AEZS-108 (AN-152) may overcome chemoresistance, which is a major drawback of systemic therapy of these malignancies by anthracyclines and other chemotherapeutic agents (11,12). The poor prognosis of pancreatic cancer is believed to be partly due to primary or secondary chemoresistance of specific subgroups of pancreatic cancer cells, namely those with an epithelial-mesenchymal transition (EMT) phenotype and cancer stem cells (20).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, these conjugates selectively affect those cells that express LHRH receptors and exert fewer side effects than unconjugated cytotoxic agents. In addition, by entering the tumor cell via a receptor-mediated internalization, resistance mechanisms like multidrug resistance-1 (MDR-1) are circumvented (11,12). LHRH agonists that have a D-Lys moiety at position 6 offer an amino side chain for a convenient attachment of various cytotoxic compounds.…”

Section: Introductionmentioning

confidence: 99%

Effective targeted chemotherapy using AEZS-108 (AN-152) for LHRH receptor-positive pancreatic cancers

Gründker

Ernst²,

Reutter³

et al. 2011

Oncol Rep

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Abstract. Pancreatic cancer is the fourth commonest cause of cancer-related mortality across the world. Because of the poor response to conventional chemotherapy, small molecules, radiation therapy and surgery, development of new targeted therapies is necessary. In the present study, we have analyzed expression of the luteinizing hormone releasing hormone (LHRH) receptor in specimens of human pancreatic cancers. Furthermore, we have investigated in vitro and in vivo whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in human pancreatic cancer cells that express LHRH receptors. LHRH receptor expression in tumor specimens of human pancreatic cancers was assessed using immunohistochemistry. Cell proliferation was analyzed using the Alamar Blue proliferation assay. Induction of apoptosis was analyzed using the TUNEL assay and quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human pancreatic tumors. Thirteen of 40 human pancreatic adenocarcinomas (32.5%) expressed LHRH receptors. We were able to show that treatment of LHRH receptor-positive MiaPaCa-2 and Panc-1 human pancreatic cancer cells with AEZS-108 (AN-152) resulted in apoptotic cell death in vitro. The antitumor effects could be confirmed in nude mice. inhibited the growth of xenotransplants of human pancreatic cancers in nude mice significantly, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for treatment of LHRH receptor-positive human pancreatic cancers with little toxicity.

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Section: Discussionmentioning

confidence: 99%

Targeted chemotherapy for triple-negative breast cancers via LHRH receptor

Föst

Duwe²,

Hellriegel³

et al. 2011

Oncol Rep

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Abstract. triple-negative breast cancer does not express estrogen and progesterone receptors and there is no overexpression/amplification of the HER2-neu gene. Therefore, this subtype of breast cancer lacks the benefits of specific therapies which target these receptors. About 60% of all human breast cancers express receptors for luteinizing hormone releasing hormone (LHRH, GnRH), which might be used as a target. The LHRH receptor can be used for targeted chemotherapy with cytotoxic luteinizing hormone releasing hormone agonists such as AEZS-108 (AN-152), in which doxorubicin is linked to ]LHRH. In the present study we have analyzed by in vitro and in vivo experiments whether the cytotoxic LHRH agonist AEZS-108 (AN-152) induces apoptosis in triple-negative human breast cancer cells that express LHRH receptors. LHRH receptor expression in tumor biopsy specimens of triple-negative breast cancers was tested using immunohistochemistry. Cell proliferation was analyzed using alamar blue proliferation assay. Induction of apoptosis was quantified by measurement of loss of mitochondrial membrane potential. In vivo experiments were performed using nude mice bearing xenografted human breast tumors. Thirty-one of 42 triple-negative breast cancers (73.8%) expressed LHRH receptors. We could show that treatment of triple-negative but LHRH-positive MDA-MB-231, HCC1806 and HCC1937 human breast cancer cells with AEZS-108 (AN-152) resulted in apoptotic cell death in vitro via activation of caspase-3. The antitumor effects were confirmed in nude mice. AEZS-108 (AN-152) inhibited the growth of xenotransplants of triple-negative human breast cancers in nude mice completely, without any apparent side effects. The cytotoxic LHRH agonist AEZS-108 (AN-152) seems to be a suitable drug for an efficacious therapy for triple-negative breast cancers with little toxicity.

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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: 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.

Cited by 26 publications

References 27 publications

Therapy of ovarian cancers with targeted cytotoxic analogs of bombesin, somatostatin, and luteinizing hormone-releasing hormone and their combinations

Therapy of ovarian cancers with targeted cytotoxic analogs of bombesin, somatostatin, and luteinizing hormone-releasing hormone and their combinations

Effective targeted chemotherapy using AEZS-108 (AN-152) for LHRH receptor-positive pancreatic cancers

Targeted chemotherapy for triple-negative breast cancers via LHRH receptor

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