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Effective targeted chemotherapy using AEZS-108 (AN-152) for LHRH receptor-positive pancreatic cancers
Carsten Gründker1, Jennifer Ernst, Madita D Reutter
1Department of Gynecology and Obstetrics, Georg-August University, Robert Koch Street 40, Göttingen 37075, Germany. grundker@med.uni-goettingen.de
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. AEZS-108 (AN-152) 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.
Insights
A novel targeted therapy, luteinizing hormone-releasing hormone (LHRH) agonist AEZS-108, shows promise for pancreatic cancer. It effectively induced apoptosis in LHRH receptor-positive pancreatic cancer cells and inhibited tumor growth in vivo with minimal toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pancreatic cancer is a leading cause of cancer mortality with limited treatment options.
- Conventional therapies often show poor response rates, necessitating novel targeted treatments.
- Luteinizing hormone-releasing hormone (LHRH) receptors are potential targets in various cancers.
Purpose of the Study:
- To investigate LHRH receptor expression in human pancreatic cancers.
- To evaluate the efficacy of the cytotoxic LHRH agonist AEZS-108 (AN-152) in LHRH receptor-positive pancreatic cancer cells.
- To assess the in vitro and in vivo anti-tumor effects and toxicity of AEZS-108.
Main Methods:
- Immunohistochemistry was used to assess LHRH receptor expression in tumor specimens.
- In vitro studies utilized alamar blue and TUNEL assays to analyze cell proliferation and apoptosis.
- In vivo efficacy and toxicity were evaluated in nude mice bearing human pancreatic tumor xenografts.
Main Results:
- LHRH receptors were expressed in 32.5% (13/40) of human pancreatic adenocarcinomas.
- AEZS-108 induced significant apoptotic cell death in LHRH receptor-positive pancreatic cancer cell lines (MiaPaCa-2, Panc-1) in vitro.
- AEZS-108 demonstrated significant inhibition of tumor xenograft growth in vivo with no apparent side effects.
Conclusions:
- LHRH receptor expression is present in a subset of human pancreatic cancers.
- The LHRH agonist AEZS-108 exhibits potent cytotoxic effects against LHRH receptor-positive pancreatic cancer.
- AEZS-108 represents a promising targeted therapeutic agent for LHRH receptor-positive pancreatic cancer with a favorable toxicity profile.
