Inhibition of U-87 MG glioblastoma by AN-152 (AEZS-108), a targeted cytotoxic analog of luteinizing hormone-releasing hormone
Metrics: PDF 1137 views | HTML 2138 views | ?
Miklos Jaszberenyi1,2,3, Andrew V. Schally1,2,3,4,5, Norman L. Block1,2,3,4, Mehrdad Nadji3, Irving Vidaurre1,2, Luca Szalontay1,2, Ferenc G. Rick1,2
1 Veterans Affairs Medical Center, Miami, FL
2 South Florida VA Foundation for Research and Education, Miami, FL 33125
3 Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL
4 Division of Hematology/Oncology, University of Miami, Miller School of Medicine, Miami, FL
5 Division of Endocrinology, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL
Andrew V. Schally, email:
Ferenc G. Rick, email:
Keywords: glioblastoma multiforme, U-87 MG, cytotoxic, LHRHor GnRH receptors, AN-152, AEZS-108, nude mice, targeted therapy
Received: March 5, 2013 Accepted: March 6, 2013 Published: March 7, 2013
Glioblastoma multiforme is the most frequent tumor of the central nervous system in adults and has a dismal clinical outcome, which necessitates the development of new therapeutic approaches. We investigated in vivo the action of the targeted cytotoxic analog of luteinizing hormone releasing hormone, AN-152 (AEZS-108) in nude mice (Ncr nu/nu strain) bearing xenotransplanted U-87 MG glioblastoma tumors. We evaluated in vitro the expression of LHRH receptors, proliferation, apoptosis and the release of oncogenic and tumor suppressor cytokines. Clinical and U-87 MG samples of glioblastoma tumors expressed LHRH receptors. Treatment of nude mice with AN-152, once a week at an intravenous dose of 413 nmol/20g, for six weeks resulted in 76 % reduction in tumor growth. AN-152 nearly completely abolished tumor progression and elicited remarkable apoptosis in vitro. Genomic (RT-PCR) and proteomic (ELISA, Western blot) studies revealed that AN-152 activated apoptosis, as reflected by the changes in p53 and its regulators and substrates, inhibited cell growth, and elicited changes in intermediary filament pattern. AN-152 similarly reestablished contact regulation as demonstrated by expression of adhesion molecules and inhibited vascularization, as reflected by the transcription of angiogenic factors. Our findings suggest that targeted cytotoxic analog AN-152 (AEZS-108) should be considered for a treatment of glioblastomas.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.