Department of Pharmacology, College of Medicine, Howard University, Washington, DC, U.S.A.
Department of Microbiology, College of Medicine, Howard University, Washington, DC, U.S.A.
Anticancer Res. 2020 Dec;40(12):6623-6635. doi: 10.21873/anticanres.14687. Epub 2020 Dec 7.
BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer (BC) and lacks targeted therapy and alternate therapeutic combinations. There is a necessity to increase disease-free survival in patients particularly within the first 5 years of diagnosis. 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone (Z285), a novel 1,4 naphthoquinone analog, has been shown to have cytotoxic activity in BC cell lines and in combination with 4-hydroxytamoxifen (4-OHT). A known metabolite of tamoxifen, was postulated to decrease cell proliferation. Thus, this study investigates the use of Z285 and 4-OHT alone or in combination as a novel therapeutic alternative for TNBC.
Cell proliferation assays were performed on MDA-MB-231, Hs578T, MCF7 and HCC1806 cell lines at varying time points with Z285 and 4-OHT alone and in combination. Furthermore, ROS activity was measured to determine the changes in oxidative stress caused by both drugs.
The results showed dose- and time-dependent decreases in proliferation for all cell lines when treated with Z285, 4-OHT and their combination. Combinatorial analysis performed at 72 h using Synergyfinder showed additive effects in MCF7, HCC1806 and Hs578T and an antagonistic response in MDA-MB-231. Z285 caused a significant increase in ROS production in three cell lines after 8 h, but HCC1806 showed no change in effect.
These promising results suggest the independent ability of each compound as a stand-alone chemotherapeutic agent, or in combinatorial therapy for the treatment of TNBC.
背景/目的：三阴性乳腺癌（TNBC）是一种侵袭性很强的乳腺癌（BC），缺乏靶向治疗和替代治疗组合。有必要提高患者的无病生存率，特别是在诊断后的前 5 年内。2,3-二氯-5,8-二甲氧基-1,4-萘醌（Z285）是一种新型的 1,4-萘醌类似物，已被证明在 BC 细胞系中具有细胞毒性活性，并与 4-羟基他莫昔芬（4-OHT）联合使用。4-OHT 是他莫昔芬的一种已知代谢物，据推测可降低细胞增殖。因此，本研究探讨了 Z285 和 4-OHT 单独或联合使用作为 TNBC 的新型治疗选择。
在不同时间点，对 MDA-MB-231、Hs578T、MCF7 和 HCC1806 细胞系进行 Z285 和 4-OHT 单独和联合的细胞增殖测定。此外，还测量了 ROS 活性，以确定两种药物引起的氧化应激变化。
结果表明，所有细胞系在接受 Z285、4-OHT 及其组合治疗时，增殖均呈剂量和时间依赖性下降。在 72 小时使用 Synergyfinder 进行的组合分析显示，MCF7、HCC1806 和 Hs578T 中存在相加作用，而 MDA-MB-231 中存在拮抗作用。Z285 在 8 小时后使三种细胞系的 ROS 产生显著增加，但 HCC1806 没有变化。
这些有希望的结果表明，每种化合物作为单一化疗药物或联合治疗 TNBC 的独立能力。
