Prostate cancer (PCa) is the second most common cancer in men and the fifth leading cause of cancer death. PCa is a complicated disease that develops and progresses over time, with prostate tissue inflammation playing an important role. Several pro-inflammatory mediators are associated with tissue inflammation in PCa. The cytokines IL-1β, IL-6 and IL-8 appear to be involved in PCa survival, inflammation, carcinogenesis, angiogenesis, and progression. Morphine is an analgesic agent widely used to alleviate cancer pain and has been described to inhibit cell proliferation of several cancer cell lines including the PCa (PC3, LNCaP, and DU145). Naloxone is an opioid agonist, which is used to reverse the effects of morphine. β-endorphin is a morphine-like peptide or endogenous morphine which acts primarily at µ-opioid receptors. β-endorphin has various actions, including analgesic, anti-inflammatory and immune-stimulatory effects. Furthermore, it can inhibit tumour cells and prevent them from transforming into metastatic cells by decreasing body stress, maintaining an active immune system, and balancing the levels of pro-inflammatory and anti-inflammatory cytokines such as IL-1β, IL-8 and IL-12. In this study, we studied the potential inhibitory effects of morphine, naloxone, and β-endorphin on the proliferation of the PC3 and LNCaP cell lines and their expression of the cytokines IL-1β, IL-6 and IL-8 upon their treatment with TNF-α.

An MTT assay was used to explore the potential cytotoxic effect of morphine, naloxone, combined naloxone and morphine, and -endorphin on LNCaP, PC3 cell lines and primary benign prostate cell at 24, 48, and 72-hour incubation periods. In addition, PC3 and LNCaP cells were challenged with TNF-α (10 ng/ml) for 24 hours with/without pre-treatment with morphine (1.0 μmol/L), naloxone (0.5 μmol/L), and β-endorphin (30 pg/ml), and the resultant expression of IL-1β, IL-6 and IL-8 was assessed using an ELISA assay.

Interestingly, both morphine and naloxone (at 1.0 and 0.5 μmol/L), as well as β-endorphin (30 pg/ml), were found to exert significant cytotoxic effects on LNCaP and PC3 cells (Figure 1). Nevertheless, all drug treatments could not affect the primary benign prostate cell in all incubation periods (Figure 1). Moreover, TNF-α alone induced significant increases in IL-1β, IL-6 and IL-8 released by both LNCaP and PC3 cells compared to the control. In both cell lines, such release was significantly inhibited upon pretreatment of the cells with morphine and naloxone at 1.0 and 0.5 μmol/L, respectively, and β-endorphin at 30 pg/ml concentration (Figure 2).

Morphine (1.0 μmol/L), naloxone (0.5 μmol/L), and β-endorphin (30 pg/ml) had a strong and significant inhibitory effect on the proliferation of PCa and had not affected the primary benign prostate cell in vitro, indicating their strong potential as beneficial anti-cancer therapies. Such assumption is supported by their ability to inhibit prostate cancer-associated inflammation, as denoted by the inhibition of the TNF-α-induced IL-6, IL-8 and IL-1β release by PC3 cells.

The current study demonstrates preliminary evidence suggesting that the use of opioids in prostate cancer management is without oncological detriment. It further supports a possible positive role for their role in PCa management strategies such as exercise promotion which would increase β-endorphin levels.