Antineoplastic effects of melatonin on a rare malignancy of mesenchymal origin: melatonin receptor-mediated inhibition of signal transduction, linoleic acid metabolism and growth in tissue-isolated human leiomyosarcoma xenografts.
Melatonin provides a circadian signal that regulates linoleic acid (LA)-dependent tumor growth. In rodent and human cancer xenografts of epithelial origin in vivo, melatonin suppresses the growth-stimulatory effects of linoleic acid (LA) by blocking its uptake and metabolism to the mitogenic agent, 13-hydroxyoctadecadienoic acid (13-HODE). This study tested the hypothesis that both acute and long-term inhibitory effects of melatonin are exerted on LA transport and metabolism, and growth activity in tissue-isolated human leiomyosarcoma (LMS), a rare, mesenchymally-derived smooth muscle tissue sarcoma, via melatonin receptor-mediated inhibition of signal transduction activity. Melatonin added to the drinking water of female nude rats bearing tissue-isolated LMS xenografts and fed a 5% corn oil (CO) diet caused the rapid regression of these tumors (0.17 +/- 0.02 g/day) versus control xenografts that continued to grow at 0.22 +/- 0.03 g/day over a 10-day period. LMS perfused in situ for 150 min with arterial donor blood augmented with physiological nocturnal levels of melatonin showed a dose-dependent suppression of tumor cAMP production, LA uptake, 13-HODE release, extracellular signal-regulated kinase (ERK 1/2), mitogen activated protein kinase (MEK), Akt activation, and [(3)H]thymidine incorporation into DNA and DNA content. The inhibitory effects of melatonin were reversible and preventable with either melatonin receptor antagonist S20928, pertussis toxin, forskolin, or 8-Br-cAMP. These results demonstrate that, as observed in epithelially-derived cancers, a nocturnal physiological melatonin concentration acutely suppress the proliferative activity of mesenchymal human LMS xenografts while long-term treatment of established tumors with a pharmacological dose of melatonin induced tumor regression via a melatonin receptor-mediated signal transduction mechanism involving the inhibition of tumor LA uptake and metabolism.
Dauchy
Robert T
RT
Laboratory of Chrono-Neuroendocrine Oncology, Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center, Louisiana Cancer Research Consortium, New Orleans, LA 70112-2699, USA. rdauchy@tulane.edu
Blask
David E
DE
Dauchy
Erin M
EM
Davidson
Leslie K
LK
Tirrell
Paul C
PC
Greene
Michael W
MW
Tirrell
Robert P
RP
Hill
Cody R
CR
Sauer
Leonard A
LA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007890:Leiomyosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019787:Linoleic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051381:Rats; D011923:Rats, Nude; D044094:Receptors, Melatonin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D044094:Receptors, Melatonin; D019787:Linoleic Acid; D000242:Cyclic AMP; D008550:Melatonin