Abstract
We have recently shown that 4-(E)-{(4-hydroxyphenylimino)-methylbenzene, 1,2-diol} (HPIMBD) and 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD), novel analogs of resveratrol (Res), selectively inhibited the proliferation of breast cancer cells. In the current study, we tested HPIMBD and TIMBD individually in combination with tamoxifen (Tam) for inhibition of growth of breast cancer cells. Tamoxifen was first tested on non-neoplastic breast epithelial cell lines and its dose that does not inhibit their growth was determined. A combination of this low dose of Tam with either of the Res analogs HPIMBD or TIMBD, resulted in synergistic inhibition of proliferation of breast cancer cells. Both estrogen receptor (ER)-positive and negative breast cancer cell lines responded to the combination. The combination resulted in a substantial decrease in IC50 values of Res analogs in all breast cancer cell lines tested. Mechanistic studies showed a synergistic increase in apoptosis and autophagy genes (beclin-1 and LC3BII/I) with the combination in ER-negative MDA-MB-231 cells. In ER-positive MCF-7 and T47D cells, the mechanism of synergy was found to be inhibition of expression of ERα and oncogene c-Myc. The combination treatment had a synergistic effect in inhibiting the colony forming and spheroid forming ability of cancer cells. Taken together, our findings indicate that a combination of Tam and Res analogs HPIMBD or TIMBD represents a novel approach to enhancing the use of Tam in therapy for breast cancers. Considering the urgent need for novel therapeutic strategies to treat ER-negative breast cancers and overcoming resistance in ER-positive cancers, this combinatorial approach is worthy of continued investigation.
Highlights
Breast cancer is the second leading cause of cancer deaths among women in the United States [1,2,3]
Our findings indicate that a combination of Tam and Res analogs HPIMBD or TIMBD represents a novel approach to enhancing the use of Tam in therapy for breast cancers
Non-neoplastic breast epithelial cell lines MCF-10A, MCF-10F and HMEC were initially treated with different doses of Tam ranging from 0.5 - 10μM in concentration and MTT cell survival assays were performed after 72 hours
Summary
Breast cancer is the second leading cause of cancer deaths among women in the United States [1,2,3]. Despite the multiple molecular targets, Tam therapy remains primarily tumoristatic and long-term Tam treatment leads to serious adverse effects such as development of endometrial cancers [23, 24, 25]. Another factor that limits the efficacy of Tam is the development of endocrine resistance [26]. Studies suggest that endocrine-resistance may account for up to onequarter of all breast cancers [26] Several mechanisms such as loss of ERα expression, mutations in ERα and activation of other survival signaling pathways have been implicated in the development of Tam resistance [27]. Combination therapies with agents of natural origin have been suggested [29,30,31]
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