oa Protective Effects of Melatonin on Cisplatin Induced Growth Inhibition of MCF-7 Breast Cancer Cells

Background: Pineal hormone melatonin (MEL) is a versatile molecule with diverse physiological roles ranging from circadian entrainment to anti-cancer effects. Clinical trials indicated that a co-application of cisplatin and melatonin improved the 1-year survival rate. Also, Futugami (2001) claimed melatonin enhances the sensitivity of an ovarian cancer cell line to cisplatin.

Objective: Here we study the anti-cancer effects of a co-application of cisplatin (CDDP, 1pM -10 mM - log10 scale) and melatonin (1pM – 100μM) on MCF-7 cells.

Methods: Cell viability was assessed through MTT assays and trypan blue exclusion tests.

Results: 1) a) CDDP causes concentration-dependent growth inhibition of MCF-7 cells at high concentrations (1–100 μM) over 24 and 48 hrs with an IC50 of 99.6 ± 5μM (24 hrs) b) Over a period of 6 days, 1uM CDDP causes significant (52.35 ± 0.64% of control) growth inhibition 2) MEL does not significantly inhibit MCF-7 cell growth over 24 hr and 6 day time points. 3) Simultaneous co-application of MEL with CDDP significantly (p ← 0.05) reverses 80?M CDDP induced growth inhibition over 24 hrs at physiological concentrations (0.1 – 10nM) (increase in growth by 21.4 ±} 1.8 %). 4) However, simultaneous co-application of MEL and CDDP does not significantly reverse the growth inhibition induced by 1μM CDDP over 6 days.

Conclusion: As reported by several labs, CDDP shows significant growth inhibition within 24 hrs only at high concentrations while long term growth inhibition is observed at low concentrations (1–10μM). The results indicate that the sub clone of MCF-7 cells used by us is melatonin “insensitive” as MEL does not have an anti-proliferative effect over the points tested. However, these cells are not completely irresponsive to MEL as MEL reverses CDDP induced growth inhibition at physiological concentrations. The question arises as to why such a “protection” is observed only at physiological concentrations. Moreover, this effect is only observed when acute cell death is induced at high concentrations and not at chronic low concentrations. To conclude, the results open up the interesting questions of the molecular basis of the protective effects of melatonin on CDDP induced cell death and melatonin “insensitivity”.