Synergistic inhibition of growth of lung carcinomas by antagonists of growth hormone-releasing hormone in combination with docetaxel.
We investigated the effect of antagonists of growth hormone-releasing hormone (GHRH) MZ-J-7-138 and JV-1-92 on H460 human non-small cell lung carcinoma (NSCLC) xenografted orthotopically into nude mice. Treatment with MZ-J-7-138 or JV-1-92 inhibited orthotopic growth of H460 NSCLC by 52-65% (P < 0.001) and was associated with a significant decrease in protein expression of K-Ras, cyclooxygenase-2 (Cox-2) and phospho-Akt (pAkt). In other experiments, treatment with MZ-J-7-138 or docetaxel reduced tumor volume of s.c. xenografted H460 human NSCLC by 30-36% (P < 0.01). The combination of MZ-J-7-138 and docetaxel resulted in a synergistic growth inhibition of H460 NSCLC xenografts of 63%. MZ-J-7-138 alone or in combination with docetaxel significantly reduced protein levels of K-Ras, Cox-2, and pAkt by 56-63%. Docetaxel given singly diminished the protein levels only of Cox-2 and did not affect K-Ras and pAkt. High-affinity binding sites, mRNA, and protein expression of pituitary GHRH receptors and its splice variant (SV) 1 were found in H460. H460 NSCLC cells contained GHRH peptide, and its growth was significantly inhibited in vitro by 10 microM MZ-J-7-138 (P < 0.001). Serum insulin-like growth factor 1 (IGF1) was not reduced by either GHRH antagonists. These findings suggest that antiproliferative effects of GHRH antagonists in H460 NSCLC are associated with down-regulation of K-Ras, Cox-2, and pAkt. In conclusion, GHRH antagonists in combination with docetaxel synergistically inhibit growth of H460 NSCLC and the expression of K-ras, Cox-2, and pAkt, which might abrogate the signal transduction pathways for cell growth stimulation and therapeutic resistance.
Hohla
Florian
F
Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Schally
Andrew V
AV
Szepeshazi
Karoly
K
Varga
Jozsef L
JL
Buchholz
Stefan
S
Köster
Frank
F
Heinrich
Elmar
E
Halmos
Gabor
G
Rick
Ferenc G
FG
Kannadka
Chandrika
C
Datz
Christian
C
Kanashiro
Celia A
CA
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D000077143:Docetaxel; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009929:Organ Size / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011863:Radioimmunoassay; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism; D018017:Receptors, Pituitary Hormone-Regulating Hormone / Q000235:genetics / Q000378:metabolism; D043823:Taxoids / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000972:Antineoplastic Agents, Phytogenic; D010750:Phosphoproteins; D012333:RNA, Messenger; D018013:Receptors, Neuropeptide; D018017:Receptors, Pituitary Hormone-Regulating Hormone; D043823:Taxoids; D000077143:Docetaxel; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); C048250:somatotropin releasing hormone receptor