Potentiation of cytotoxic chemotherapy by growthhormone-releasing hormone agonists

Miklos Jaszberenyi, Ferenc G. Rick, Petra Popovics, Norman L Block, Marta Zarandi, Ren Zhi Cai, Irving Vidaurre, Luca Szalontay, Arumugam R. Jayakumar, Andrew V Schally

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Abstract

The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activitiesof growth hormone-releasing hormone (GHRH), we hypothesizedthat pretreatment with a GHRH agonist, JI-34, might increase thesusceptibility of U-87 MG glioblastoma multiforme (GBM) cells tosubsequent treatment with the cytotoxic drug, doxorubicin (DOX).This concept was corroborated by our findings, in vivo, showingthat the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice,more than DOX alone. In vitro, the pretreatment of GBM cells withJI-34 potentiated inhibitory effects of DOX on cell proliferation,diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide proliferation assay, ApoLive-Glo multiplex assay,and cell volumetric assay. Proteomic studies further revealed thatthe pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen,nestin, and up-regulating the glial maturation marker, GFAP. TheGHRH agonist also reduced the release of humoral regulators ofglial growth, such as FGF basic and TGF|S. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptoticactivity (increase in p53, decrease in v-myc and Bc/-2)and anti-invasive potential (decrease in integrin a3) of the combination ofGHRH agonist and DOX. These findings indicate that the GHRHagonists can potentiate the anticancer activity of the traditionalchemotherapeutic drug, DOX, by multiple mechanisms includingthe induction of differentiation of cancer cells.

Original languageEnglish
Pages (from-to)781-786
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number2
DOIs
StatePublished - Jan 22 2014

Fingerprint

Doxorubicin
Growth Hormone-Releasing Hormone
Hormones
Drug Therapy
Glioblastoma
Proteomics
Nestin
Growth
Bromides
Cell Size
Nude Mice
Integrins
Brain Neoplasms
Neuroglia
Pharmaceutical Preparations
Cell Differentiation
Neoplasms
Cell Survival
Stem Cells
Cell Proliferation

Keywords

  • Peptide analogs
  • Targeted therapy

ASJC Scopus subject areas

  • General

Cite this

Potentiation of cytotoxic chemotherapy by growthhormone-releasing hormone agonists. / Jaszberenyi, Miklos; Rick, Ferenc G.; Popovics, Petra; Block, Norman L; Zarandi, Marta; Cai, Ren Zhi; Vidaurre, Irving; Szalontay, Luca; Jayakumar, Arumugam R.; Schally, Andrew V.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 2, 22.01.2014, p. 781-786.

Research output: Contribution to journalArticle

Jaszberenyi, M, Rick, FG, Popovics, P, Block, NL, Zarandi, M, Cai, RZ, Vidaurre, I, Szalontay, L, Jayakumar, AR & Schally, AV 2014, 'Potentiation of cytotoxic chemotherapy by growthhormone-releasing hormone agonists', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 2, pp. 781-786. https://doi.org/10.1073/pnas.1322622111
Jaszberenyi, Miklos ; Rick, Ferenc G. ; Popovics, Petra ; Block, Norman L ; Zarandi, Marta ; Cai, Ren Zhi ; Vidaurre, Irving ; Szalontay, Luca ; Jayakumar, Arumugam R. ; Schally, Andrew V. / Potentiation of cytotoxic chemotherapy by growthhormone-releasing hormone agonists. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 2. pp. 781-786.
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