Abstract
(−)-Epigallocatechin-3-gallate (EGCG) and chemotherapeutic agents cotreatment can improve cytotoxicity against cancer cells. We showed that EGCG and the rexinoid 6-OH-11-O-hydroxyphenanthrene (IIF), given together, were cytotoxic toward MCF-7, MCF-7TAM, and MDA-MB-231, three breast carcinoma cell lines showing different molecular characteristics. Cell growth arrest and apoptosis were greater after EGCG and IIF cotreatment than after individual administration. Cytotoxicity was related to upregulation of 67-kDa laminin receptor (LR67), one of the principal molecular targets of EGCG, and activation of the nuclear retinoic X receptors (RXRs) pathway. Furthermore, the transcription factor Forkhead box O3 (Foxo3a), a protein able to trigger apoptosis through upregulation of genes necessary for cell death, was activated. EGCG and IIF cotreatment produced a significant nuclear import of Foxo3a from the cytoplasm in MCF-7, MCF-7TAM, and MDA-MB-231 cells. In MCF-7TAM cells only, Foxo3a nuclear localization was associated with p473AKT downregulation. For the first time we showed that when EGCG and IIF, two harmless molecules, were given together, they might increase cytotoxicity in three breast carcinoma cell lines, two of them being representative of poorly responsive breast carcinoma types.
Highlights
Breast cancer is the most common cancer diagnosed in women worldwide: incidence rates are highest in Western Europe and lowest in Eastern and Middle Africa
We investigated whether EGCG and IIF, administered individually and in combination, could vary the expression of their molecular targets laminin receptor 67 kD (LR67) (EGCG) and retinoic X receptors (RXRs) (IIF), respectively, and whether the resulting cytotoxicity could be assigned to increase in molecular targets availability
We explored the cytotoxicity of EGCG, the most important catechin of green tea, and IIF, a RXR ligand under investigation in cancer therapy, given individually and in combination with three breast carcinoma cell lines: MCF-7, MCF-7TAM, and MDA-MB-231 cells
Summary
Breast cancer is the most common cancer diagnosed in women worldwide: incidence rates are highest in Western Europe and lowest in Eastern and Middle Africa. Different treatment options and protocols are considered for each stage and type of breast cancer, including the use of systemic chemotherapy drugs, cytotoxic for both normal and malignant cycling cells. Numerous in vitro and animal studies suggest that green tea catechins may play a role in lowering risk and upset of several chronic diseases, especially diabetes, cardiovascular diseases [1, 2], and cancer [3, 4]. LR67 siRNA downregulation attenuated EGCG cytotoxicity [14] These studies demonstrated that LR67 was a pivotal molecule leading to cell death after EGCG treatment and they first pinpointed that the combination of EGCG and a synthetic retinoid could be a promising strategy to be investigated in cancer prevention and treatment
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