Molecular Pathology and Pharmacology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW, Australia.
Atta-ur Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan.
Br J Pharmacol. 2020 May;177(10):2365-2380. doi: 10.1111/bph.14985. Epub 2020 Feb 12.
Breast cancer is the leading cause of death in women worldwide, with resistance to current therapeutic strategies, including tamoxifen, causing major clinical challenges and leading to more aggressive and metastatic disease. To address this, novel strategies that can inhibit the mechanisms responsible for tamoxifen resistance need to be assessed.
We examined the effect of the novel, clinically-trialled, thiosemicarbazone anti-cancer agent, DpC, and its potential as a combination therapy with the clinically used estrogen receptor (ER) antagonist, tamoxifen, using both tamoxifen-resistant and -sensitive, human breast cancer cells (MDA-MB-453, MDA-MB-231 and MCF-7) in 2D and 3D cell-culture. Synergy was assessed using the Chou-Talalay method. The molecular and anti-proliferative effects of these agents and their combination was examined via Western blot, immunofluorescence and colony formation assays.
Combinations of tamoxifen with DpC were highly synergistic, leading to potent inhibition of cell proliferation, colony formation, and ER-α transcriptional activity. The combination also more efficiently reduced major molecular drivers of proliferation of tamoxifen-resistant cells, including c-Myc, cyclin D1, and p-AKT, while up-regulating the cell cycle inhibitor, p27, and inhibiting oncogenic phosphorylation of ER-α at Ser167. Assessing these effects using 3D cell culture further confirmed the greater effects of DpC combined with tamoxifen in reducing ER-α expression, and that of the proliferation marker, Ki-67, in both tamoxifen-sensitive and -resistant MCF-7 spheroids.
These studies demonstrate that the synergistic combination of DpC with tamoxifen could be a promising new therapeutic strategy to overcome tamoxifen resistance in ER-positive breast cancer.
乳腺癌是全球女性死亡的主要原因，对当前治疗策略（包括他莫昔芬）的耐药性导致了重大的临床挑战，并导致疾病更具侵袭性和转移性。为了解决这个问题，需要评估能够抑制导致他莫昔芬耐药的机制的新策略。
我们研究了新型临床试用的噻唑烷酮类抗癌药物 DpC 及其与临床使用的雌激素受体（ER）拮抗剂他莫昔芬联合治疗的效果，使用 2D 和 3D 细胞培养中的两种他莫昔芬耐药和敏感的人乳腺癌细胞（MDA-MB-453、MDA-MB-231 和 MCF-7）。使用 Chou-Talalay 方法评估协同作用。通过 Western blot、免疫荧光和集落形成实验检测这些药物及其组合的分子和抗增殖作用。
他莫昔芬与 DpC 的联合具有高度协同作用，可有效抑制细胞增殖、集落形成和 ER-α 转录活性。该联合还更有效地降低了他莫昔芬耐药细胞的主要增殖驱动分子，包括 c-Myc、cyclin D1 和 p-AKT，同时上调细胞周期抑制剂 p27，并抑制 ER-α 在 Ser167 的致癌磷酸化。使用 3D 细胞培养评估这些作用进一步证实了 DpC 与他莫昔芬联合在降低 ER-α 表达方面的更大作用，以及增殖标志物 Ki-67 在他莫昔芬敏感和耐药 MCF-7 球体中的作用。
这些研究表明，DpC 与他莫昔芬的协同联合可能是克服 ER 阳性乳腺癌中他莫昔芬耐药的一种很有前途的新治疗策略。
