Melatonin potentiates the antitumor effect of curcumin by inhibiting IKKβ/NF-κB/COX-2 signaling pathway

Abstract

Curcumin, a natural polyphenolic compound, has commonly been used as a food additive or in many traditional medicine remedies for over 2,000 years in many Asian countries. Melatonin is a hormone secreted from pineal glands of mammals and possesses diverse physiological functions. Both curcumin and melatonin have the effective potential to inhibit proliferation of various types of cancers, but there is no report on their combination for bladder cancer treatment, and the underlying mechanism remains poorly understood. In the present study, we investigated whether the combination of curcumin and melatonin leads to an enhanced inhibition of cell proliferation in bladder cancer cells. Our results showed that the combinational treatment enhanced the repression of nuclear translocation of NF-κB and their binding on COX-2 promoter via inhibiting IKKβ activity, resulting in inhibition of COX-2 expression. In addition, combined treatment with curcumin and melatonin induced cell apoptosis in bladder cancer through enhancing the release of cytochrome c from the mitochondrial intermembrane space into the cytosol. These results, therefore, indicated that melatonin synergized the inhibitory effect of curcumin against the growth of bladder cancer by enhancing the anti-proliferation, anti-migration, and pro-apoptotic activities, and provide strong evidence that combined treatment with curcumin and melatonin might exhibit an effective therapeutic option in bladder cancer therapy.

Melatonin and inflammation—Story of a double‐edged blade

“…Apart from NO, which has been extensively discussed above, some of these regulators are relevant to inflammation and to melatonin's anti‐inflammatory actions as well (Figure ). Melatonin has been shown many times to inhibit NF‐κB signaling and this had been convincingly related to the attenuation of inflammatory responses, under various experimental conditions . In particular, this effect was found to be decisive in the downregulation of two relevant proinflammatory factors, iNOS and COX‐2 (cyclooxygenase‐2) .…”

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

“…Many studies have observed that melatonin treatment has beneficial effects on normal cells but induces apoptosis in tumor cells (70)(71)(72)(73)(74). Under melatonin treatment, large quantity of cytochrome C is released from the mitochondria into cytosol to induce apoptosis in tumor cells (75)(76)(77) while and the cytochrome C release is inhibited in the normal cells by melatonin (75,(78)(79)(80).…”

Curcumin and Endometriosis

“…Few studies have focused on the potential interaction of curcumin and melatonin in endometriosis. However, recent findings have shown that co-treatment of melatonin and curcumin can decrease COX-2 expression and can repress the NF-kappaB pathway [189]. Moreover, this combination can inhibit MMP-2, MMP-9 and TIMP-2 expression [189].…”

“…However, recent findings have shown that co-treatment of melatonin and curcumin can decrease COX-2 expression and can repress the NF-kappaB pathway [189]. Moreover, this combination can inhibit MMP-2, MMP-9 and TIMP-2 expression [189]. Curcumin can activate sirtuin 1 (SIRT1) [134].…”