Sanchez Yamila, Vasquez Callejas Mariana Abigail, Miret Noelia Victoria, Rolandelli Gabino, Costas Catalina, Randi Andrea Silvana, Español Alejandro
Center of Pharmacological and Botanical Studies (CEFYBO)-National Council for Science and Technology (CONICET)-University of Buenos Aires, Buenos Aires C1121ABG, Argentina.
Laboratory of Biological Effects of Environmental Pollutants, Department of Human Biochemistry, School of Medicine, University of Buenos Aires, Buenos Aires C1121ABG, Argentina.
Explor Target Antitumor Ther. 2024;5(2):278-295. doi: 10.37349/etat.2024.00218. Epub 2024 Mar 21.
Triple negative breast cancer (TNBC) is usually treated with high doses of paclitaxel, whose effectiveness may be modulated by the action of environmental contaminants such as hexachlorobenzene. High doses of paclitaxel cause adverse effects such as low cellular selectivity and the generation of resistance to treatment due to an increase in the expression of multidrug resistance proteins (MRPs). These effects can be reduced using a metronomic administration scheme with low doses. This study aimed to investigate whether hexachlorobenzene modulates the response of cells to conventional chemotherapy with paclitaxel or metronomic chemotherapy with paclitaxel plus carbachol, as well as to study the participation of the MRP ATP-binding cassette transporter G2 (ABCG2) in human TNBC MDA-MB231 cells.
Cells were treated with hexachlorobenzene alone or in combination with conventional or metronomic chemotherapies. The effects of treatments on cell viability were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the nuclear factor kappa B pathway participation was evaluated using a selective inhibitor. ABCG2 expression and its modulation were determined by western blot.
Results confirmed that paclitaxel reduces MDA-MB231 cell viability in a concentration-dependent manner. Results also showed that both conventional and metronomic chemotherapies reduced cell viability with similar efficacy. Although hexachlorobenzene did not modify cell viability , it did reverse the effect induced by the conventional chemotherapy, without affecting the efficacy of the metronomic chemotherapy. Additionally, a differential modulation of ABCG2 expression was determined, mediated by the nuclear factor kappa B pathway, which was directly related to the modulation of cell sensitivity to another cycle of paclitaxel treatment.
The findings indicate that, in human TNBC MDA-MB231 cells, in the presence of hexachlorobenzene, the metronomic combination of paclitaxel plus carbachol is more effective in affecting the tumor biology than the conventional therapeutic administration scheme of paclitaxel.
三阴性乳腺癌（TNBC）通常采用高剂量紫杉醇治疗，其疗效可能会受到六氯苯等环境污染物作用的调节。高剂量紫杉醇会导致诸如细胞选择性低以及因多药耐药蛋白（MRP）表达增加而产生治疗抗性等不良反应。使用低剂量的节拍式给药方案可减少这些影响。本研究旨在探究六氯苯是否会调节细胞对常规紫杉醇化疗或紫杉醇加卡巴胆碱节拍式化疗的反应，以及研究MRP ATP结合盒转运体G2（ABCG2）在人TNBC MDA-MB231细胞中的作用。
细胞单独用六氯苯处理，或与常规或节拍式化疗联合处理。通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐试验测定处理对细胞活力的影响，并使用选择性抑制剂评估核因子κB途径的参与情况。通过蛋白质免疫印迹法测定ABCG2的表达及其调节情况。
结果证实紫杉醇以浓度依赖性方式降低MDA-MB231细胞活力。结果还表明，常规化疗和节拍式化疗降低细胞活力的效果相似。尽管六氯苯未改变细胞活力，但它确实逆转了常规化疗诱导的效应，而不影响节拍式化疗的疗效。此外，确定了由核因子κB途径介导的ABCG2表达的差异调节，这与细胞对另一轮紫杉醇治疗的敏感性调节直接相关。
研究结果表明，在人TNBC MDA-MB231细胞中，在存在六氯苯的情况下，紫杉醇加卡巴胆碱的节拍式联合用药在影响肿瘤生物学方面比紫杉醇的常规治疗给药方案更有效。
