Neoplastic events can be marked by uncontrolled cell proliferation, and thus, one major focus of cancer research has been to identify treatments which reduce or inhibit cell growth. Over the years, various compounds, both naturally occurring and chemically synthesized, have been utilized to inhibit neoplastic cell proliferation. Two such oncostatic agents, melatonin and retinoic acid, have been shown to suppress the growth of hormone-responsive breast cancer in a similar time-course. Currently, separate clinical protocols exist for the administration of retinoids and melatonin as adjuvant therapies for cancer. In vitro studies were conducted to examine effects of a sequential treatment regimen of melatonin followed 24 hours later by retinoic acid (RA) on the proliferation of the estrogen receptor (ER)-positive MCF-7 human breast tumor cells line Incubation of hormonally-responsive MCF-7 and T47D cells with melatonin (10--9 M) followed 24 hours later by RA (10--9 M) resulted in the complete cessation of cell proliferation and induction of apoptosis as was evidenced by the formation of a ladder of nucleosomal oligomers when viewed by agarose gel electrophoresis. The apoptotic effect of this sequential treatment with melatonin and RA appears to be both cell and regimen specific since (a) ER-negative MDA-MB-231 and BT-20 breast tumor cells were unaffected, and (b) the simultaneous administration of melatonin and RA was not associated with apoptosis in any of the breast cancer cell lines studied. Furthermore, no induction of a cytocidal effect is observed in cells pre-treated with RA followed by melatonin, suggesting that melatonin is priming the cells to the effects of RA. There also appears to be a minimum pre-treatment time with melatonin of 12 h necessary in order to induce the apoptotic effect. It has been shown also that pre-treatment of MCF-7 cells for 24 hours with melatonin sensitizes the cells to the effects of RA, and that a much lower concentration of RA can be used to induce an apoptotic effect. This sensitization of the cells to RA is not due to up-regulation of RAR or RXR expression since Western blot analysis demonstrated no change in expression of RAR or RXR in response to treatment with melatonin and RA. The sequential treatment regimen of melatonin followed by RA induced cytocidal effects in MCF-7 cells by activating pathways leading to apoptosis. This was evidenced by decreased ER and Bcl-2 as well as increased Bak and Bax expression. Taken together, the results suggest that use of an appropriate regimen of melatonin and RA inhibits the proliferation and induces apoptosis in ER-positive human breast cancer, and should be considered for pre-clinical and clinical evaluation against ER-positive human breast cancer / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_27203 |
| Date | January 1999 |
| Contributors | Enriquez, Kristin Mary-Eleanor Eck (Author), Hill, Steven M (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Rights | Access requires a license to the Dissertations and Theses (ProQuest) database., Copyright is in accordance with U.S. Copyright law |
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