College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, United States of America.
PLoS One. 2019 Oct 30;14(10):e0215269. doi: 10.1371/journal.pone.0215269. eCollection 2019.
Drug resistance is the leading cause of breast cancer-related mortality in women, and triple negative breast cancer (TNBC) is the most aggressive subtype, affecting African American women more aggressively compared to Caucasians women. Of all cancer-related deaths, 15 to 20% are associated with inflammation, where proinflammatory cytokines have been implicated in the tumorigenesis process. The current study investigated the effects of the polyphenolic compound butein (2',3,4,4'-tetrahydroxychalcone) on cell proliferation and survival, as well as its modulatory effect on the release of proinflammatory cytokines in MDA-MB-231 (Caucasian) and MDA-MB-468 (African American) TNBC cell. The results obtained showed that butein decreased cell viability in a time and dose-dependent manner, and after 72-h of treatment, the cell proliferation rate was reduced in both cell lines. In addition, butein was found to have higher potency in MDA-MB-468, exhibiting anti-proliferative effects in lower concentrations. Apoptosis assays demonstrated that butein (50 μM) increased apoptotic cells in MDA MB-468, showing 60% of the analyzed cells in the apoptotic phase, compared to 20% in MDA-MB-231 cells. Additionally, butein downregulated both protein and mRNA expression of the proinflammatory cytokine, CCL2, and IKBKE in TNFα-activated Caucasian cells, but not in African Americans. This study demonstrates butein potential in cancer cell suppression showing a higher cytotoxic, anti-proliferative, and apoptotic effects in African Americans, compared to Caucasians TNBC cells. It also reveals the butein inhibitory effect on CCL2 expression with a possible association with IKBKE downregulation in MDA-MB-231 cells only, indicating that Caucasians and African Americans TNBC cells respond differently to butein treatment. The obtained findings may provide an explanation regarding the poor therapeutic response in African American patients with advanced TNBC.
耐药性是导致女性乳腺癌相关死亡的主要原因，而三阴性乳腺癌（TNBC）是最具侵袭性的亚型，与高加索女性相比，非洲裔美国女性的侵袭性更强。在所有与癌症相关的死亡中，有 15%至 20%与炎症有关，其中促炎细胞因子被认为与肿瘤发生过程有关。本研究调查了多酚化合物布地醇（2'，3，4，4'-四羟基查耳酮）对细胞增殖和存活的影响，以及其对 MDA-MB-231（高加索）和 MDA-MB-468（非洲裔美国）TNBC 细胞中促炎细胞因子释放的调节作用。结果表明，布地醇呈时间和剂量依赖性方式降低细胞活力，并且在 72 小时处理后，两种细胞系的细胞增殖率均降低。此外，布地醇在 MDA-MB-468 中显示出更高的效力，在较低浓度下表现出抗增殖作用。凋亡测定表明，布地醇（50μM）增加了 MDA-MB-468 中的凋亡细胞，分析的细胞中有 60%处于凋亡阶段，而 MDA-MB-231 细胞中只有 20%。此外，布地醇下调了 TNFα 激活的高加索细胞中促炎细胞因子 CCL2 和 IKBKE 的蛋白和 mRNA 表达，但对非洲裔美国人没有影响。本研究表明布地醇在抑制癌细胞方面具有潜力，与高加索人 TNBC 细胞相比，其在非洲裔美国人中表现出更高的细胞毒性、抗增殖和凋亡作用。它还揭示了布地醇对 CCL2 表达的抑制作用，与 MDA-MB-231 细胞中 IKBKE 下调可能存在关联，表明高加索人和非洲裔美国人 TNBC 细胞对布地醇治疗的反应不同。这些发现可能为解释非洲裔美国晚期 TNBC 患者治疗反应不佳提供了依据。
