Anti-cancer effects of morphine through inhibition of tumour necrosis factor-alpha release and mRNA expression

Morphine is mainly used to relieve pain in the terminal stage of cancer patients. We found that morphine has inhibitory effects on growth of various human cancer cell lines, with IC50 from 2.7 to 8.8 mM, and BALB/3T3 cells, with IC50 of 1.5 mM. Although the IC50 values were relatively high, we decided to study the mechanisms of anti-carcinogenic effects of morphine. Morphine inhibited activation of protein kinase C induced by teleocidin, one of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumour promoters (IC50, 1 mM). Based on our previous evidence that tumour necrosis factor-alpha (TNF-alpha) acts as an endogenous tumour promoter on BALB/3T3 cells initiated with 3-methylcholanthrene, we found that morphine dose-dependently inhibited TnF-alpha release from KATO III cells (IC50, 5.6 mM) and also from BALB/3T3 cells (IC50, 1.3 mM) induced by okadaic acid, one of the non-TPA type tumour promoters. Moreover, morphine inhibited expression of TNF-alpha mRNA in BALB/3T3 cells (IC50, 1.6 mM), but not expression of early response genes. Morphine may improve condition of cancer patients by suppression of tumour growth and reduction of amounts of an endogenous tumor promoter, TNF-alpha, in tissues. The high dosage of morphine required to induce anticarcinogenic effects is also discussed.