title: Potentiating effects of GHRH analogs on the response to chemotherapy.
abstract: Growth hormone releasing hormone (GHRH) from hypothalamus nominatively stimulates growth hormone release from adenohypophysis. GHRH is also produced by cancers, acting as an autocrine/paracrine growth factor. This growth factor function is seen in lymphoma, melanoma, colorectal, liver, lung, breast, prostate, kidney, bladder cancers. Pituitary type GHRH receptors and their splice variants are also expressed in these malignancies. Synthetic antagonists of the GHRH receptor inhibit proliferation of cancers. Besides direct inhibitory effects on tumors, GHRH antagonists also enhance cytotoxic chemotherapy. GHRH antagonists potentiate docetaxel effects on growth of H460 non-small cell lung cancer (NSCLC) and MX-1 breast cancer plus suppressive action of doxorubicin on MX-1 and HCC1806 breast cancer. We investigated mechanisms of antagonists on tumor growth, inflammatory signaling, doxorubicin response, expression of drug resistance genes, and efflux pump function. Triple negative breast cancer cell xenografted into nude mice were treated with GHRH antagonist, doxorubicin, or their combination. The combination reduced tumor growth, inflammatory gene expression, drug-resistance gene expression, cancer stem-cell marker expression, and efflux-pump function. Thus, antagonists increased the efficacy of doxorubicin in HCC1806 and MX-1 tumors. Growth inhibition of H460 NSCLC by GHRH antagonists induced marked downregulation in expression of prosurvival proteins K-Ras, COX-2, and pAKT. In HT-29, HCT-116 and HCT-15 colorectal cancer lines, GHRH antagonist treatment caused cellular arrest in S-phase of cell cycle, potentiated inhibition of in vitro proliferation and in vivo growth produced by S-phase specific cytotoxic agents, 5-FU, irinotecan and cisplatin. This enhancement of cytotoxic therapy by GHRH antagonists should have clinical applications.
authors: a Veterans Affairs Medical Center and South Florida VA Foundation for Research and Education ; Miami , FL USA.
authors: Andrew V
authors: AV
authors: Schally
authors: Roberto
authors: R
authors: Perez
authors: Norman L
authors: NL
authors: Block
authors: Ferenc G
authors: FG
authors: Rick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008819:Mice, Nude; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054440:Receptors, Ghrelin
keywords: antagonist; breast cancer; chemotherapy; combination therapy; drug resistance; growth factor; growth-hormone-releasing hormone; neuropeptide; prostate cancer; targeted therapy
references: Oncol Rep. 2013 Jul;30(1):413-8
references: 23624870
references: Prostate. 2012 Apr;72(5):555-65
references: 21796649
references: Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):781-6
references: 24379381
references: Genomics. 2006 Jan;87(1):113-8
references: 16311016
references: Prostate. 2011 May 15;71(7):736-47
references: 20945403
references: Peptides. 2014 Feb;52:104-12
references: 24373935
references: Int J Oncol. 2011 Oct;39(4):1025-32
references: 21701777
references: Horm Metab Res. 2010 Oct;42(11):781-6
references: 20665426
references: Oncotarget. 2012 Sep;3(9):988-97
references: 22941871
references: Expert Opin Pharmacother. 2013 Nov;14(16):2237-47
references: 23984804
references: Proc Natl Acad Sci U S A. 2013 Feb 12;110(7):2617-22
references: 23359692
references: World J Gastroenterol. 2014 May 28;20(20):6102-12
references: 24876732
references: Nat Clin Pract Endocrinol Metab. 2008 Jan;4(1):33-43
references: 18084344
references: Oncotarget. 2012 Jul;3(7):686-99
references: 22824624
references: BMC Cancer. 2014;14:847
references: 25410881
references: BMC Cancer. 2011;11:130
references: 21486440
references: Cancer Lett. 2013 Sep 10;338(1):63-8
references: 22634497
references: Cell Cycle. 2014;13(17):2790-7
references: 25486366
references: J Cancer Res Clin Oncol. 2012 Mar;138(3):387-95
references: 22160161
references: Peptides. 2010 Oct;31(10):1839-46
references: 20633588
references: Prostate. 2013 Jun;73(8):873-83
references: 23280565
references: Oncogene. 2009 Aug 20;28(33):2940-7
references: 19581928
references: Nature. 2002 Dec 19-26;420(6917):860-7
references: 12490959
references: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1943-6
references: 17261802
references: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14513-8
references: 16983095
references: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3755-60
references: 21321192
references: Oncotarget. 2014 Jun 30;5(12):4567-78
references: 24994120
references: Oncotarget. 2013 Mar;4(3):422-32
references: 23518876
references: Anticancer Drugs. 2009 Aug;20(7):553-8
references: 19491659
references: Cytokine. 2008 Sep;43(3):374-9
references: 18701317
references: EMBO Mol Med. 2009 Sep;1(6-7):303-14
references: 20049734
references: Urol Oncol. 2015 Jun;33(6):270-4
references: 25512159
references: Peptides. 2009 Sep;30(9):1643-50
references: 19524629
references: Anticancer Drugs. 2013 Feb;24(2):150-7
references: 23080077
references: Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):1084-9
references: 24395797
references: Cell Cycle. 2009 Oct 1;8(19):3149-56
references: 19755849
references: J Urol. 2012 Apr;187(4):1498-504
references: 22341819
references: Exp Biol Med (Maywood). 2011 Sep;236(9):1022-9
references: 21856755
references: Nat Clin Pract Endocrinol Metab. 2007 Feb;3(2):157-67
references: 17237842
references: Prostate. 2008 Dec 1;68(16):1763-72
references: 18729085
references: J Biol Chem. 2010 Oct 8;285(41):31100-6
references: 20705611
references: Science. 1982 Nov 5;218(4572):585-7
references: 6812220
references: Horm Metab Res. 2011 Oct;43(11):816-20
references: 22009378
references: Int J Oncol. 2012 Feb;40(2):461-8
references: 21922131
references: Breast Cancer Res. 2007;9(4):212
references: 17705880
references: Oncoscience. 2014 Oct 24;1(10):665-73
references: 25593995
references: Cancer Biol Ther. 2010 Feb;9(4):295-302
references: 20026903
references: Curr Drug Deliv. 2011 Jan;8(1):11-25
references: 21034424
references: Oncotarget. 2013 May;4(5):751-60
references: 23744510
references: Ann Surg Oncol. 2008 Feb;15(2):407-14
references: 18043974
references: J Cell Physiol. 2007 Nov;213(2):374-83
references: 17680632
references: Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1655-60
references: 22307626
references: Cell Cycle. 2012 Nov 15;11(22):4203-10
references: 23095641
references: Target Oncol. 2013 Dec;8(4):281-90
references: 23371031
references: Cell Cycle. 2012 Jul 1;11(13):2518-25
references: 22751419