Abstracts
Singular and Combined Effects of the Anti-estrogen Tamoxifen, the isoflavone Genistein, and the Nuclear Factor Kappa B (NF-kB) inhibitor Parthenolide in the Treatment of the Estrogen Receptor Positive Primary Breast Carcinoma Cell Line MCF-7.
Alarming statistics and poor prospects have made breast cancer one of the priorities of ongoing international research. During this investigation, the response of MCF-7 breast cancer cells grown in vitro as multicellular tumor spheroids to several agents were analyzed as part of the experimental pre-clinical studies currently ongoing in the SCSU cancer research laboratory.
The effects of the anti-estrogen tamoxifien, used for more than 20 years as adjuvant therapy in breast cancer treatment, were analyzed individually and in combination with the phytoestrogen genistein and the novel NF-kB inhibitor parthenolide. The latter anti-inflammatory herbal products was also evaluated individually and in combination with isoflavone genistein and the conventional chemotherapeutic drug Taxol (paclitaxel). These singular and combined treatment approaches were performed under conditions of high versus low level of beta estadiol in order to explore the role of the hormone on the cell response to the drugs.
The result obtained indicated that the sensitivity of MCF-7 breast cancer cells to tamoxifen increased significantly when levels of circulating estrogen were higher, suggesting that the growth inhibiton caused by the drug is estrogen-dependent. In contrast, genistein's growth inhibitory effects were observed to be estrogen independent, which is consistent with data obtained by many studies that have shown that the effects of genistein in breast cancer cells are not limited to estrogen receptor positive tumors. Synergistic effects were produced by the combination of genistein and tamoxifen.
A comparison of the responses of the NF-kB inhibitor parthenolide in breast cancer spheroid with those produced by placlitaxel, showed that at similar low doses the experimental agent parthenolide was more effective than the chemotherapeutic drug causing complete cytotoxic effects. Parthenolide in combination with genistein produced significant synergistic effects, which were estrogen independent. However, combinations of parthenolide and tamoxifen caused complete cytotoxic effects on MCF-7 solid tumors when estrogen levels were increased, pointing out the dependence of tamoxifen on the availability of the hormone to achieve optimal results.
Potential clinical applications are drawn from these observations. Combined treatments of genistein and tamoxifen, and latter with parthenolide may be of benefit in clinical trials against estrogen receptor positive tumors principally in women whose levels of circulating estrogen are relatively high. Combination therapies using genistein and parthenolide might be effective in the treatment of estrogen receptor positive tumors independently of estrogen levels.
Singular and Combined Effects of the Isoflavone Genistein and the Retinoid All-Trans Retonoic on Multicellular Tumor Spheroids of the Estrogen Receptor Positive Primary Breast Carcinoma Cell Line MCF-7.
Genistein is a phytoestrogen demonstrated to have both growth enhancing and growth inhibitory effects on estrogen receptor positive and estrogen receptor negative breast carcinoma cell lines. All-trans-retonoic acid, ATRA, is a vitamin A derivative shown to inhibit cell proliferation and survival in a variety of breast cancer cell lines. Many cellular pathways have been implicated in the growth inhibitory and cytotoxic responses elicited by these agents. This research study involved a comparison of the growth inhibitory and cytotoxic effects of genistein alone or in combination with ATRA as well as ATRA used as the sole agent in the treatment of the estrogen receptor positive primary breast Carcinoma cell line MCF-7 cultured as traditional monolayer configuration and as multicellular tumor spheroids.