Marques Maiara Bernardes, Andrade Filipe Reis Teodoro, Silva Estela Fernandes E, Oliveira Bruno Rodrigues, Almeida Daniela Volcan, de Souza Votto Ana Paula, Marins Luis Fernando
Laboratory of Molecular Biology, Institute of Biological Sciences, Federal University of Rio Grande -FURG, Rio Grande, RS, Brazil.
Laboratory of Cell Culture, Institute of Biological Sciences, Federal University of Rio Grande -FURG, Rio Grande, RS, Brazil.
Mol Cell Biochem. 2023 Nov;478(11):2489-2496. doi: 10.1007/s11010-023-04678-3. Epub 2023 Mar 2.
In this work, we identified that different chemotherapeutic drugs may select cells with different antioxidant capacities. For this, we evaluated the sensitivity of two multidrug-resistant (MDR) erythroleukemia cell lines: Lucena (resistant to vincristine, VCR) and FEPS (resistant to daunorubicin, DNR) derived from the same sensitive cell K562 (non-MDR) to hydrogen peroxide. In addition, we evaluated how the cell lines respond to the oxidizing agent in the absence of VCR/DNR. In absence of VCR, Lucena drastically decreases cell viability when exposed to hydrogen peroxide, while FEPS is not affected even without DNR. To analyze whether selection by different chemotherapeutic agents may generate altered energetic demands, we analyzed the production of reactive oxygen species (ROS) and the relative expression of the glucose transporter 1 gene (glut1). We observed that the selection through DNR apparently generates a higher energy demand than VCR. High levels of transcription factors genes expression (nrf2, hif-1α, and oct4) were kept even when the DNR is withdrawn from the FEPS culture for one month. Together, these results indicate that DNR selects cells with greater ability to express the major transcription factors related to the antioxidant defense system and the main extrusion pump (ABCB1) related to the MDR phenotype. Taking into account that the antioxidant capacity of tumor cells is closely related to resistance to multiple drugs, it is evident that endogenous antioxidant molecules may be targets for the development of new anticancer drugs.
在这项研究中，我们发现不同的化疗药物可能会选择具有不同抗氧化能力的细胞。为此，我们评估了两种多药耐药（MDR）红白血病细胞系对过氧化氢的敏感性：Lucena（对长春新碱，VCR耐药）和FEPS（对柔红霉素，DNR耐药），它们均源自同一敏感细胞K562（非MDR）。此外，我们评估了这些细胞系在不存在VCR/DNR的情况下对氧化剂的反应。在不存在VCR的情况下，Lucena暴露于过氧化氢时细胞活力急剧下降，而FEPS即使在不存在DNR的情况下也不受影响。为了分析不同化疗药物的选择是否会产生能量需求的改变，我们分析了活性氧（ROS）的产生以及葡萄糖转运蛋白1基因（glut1）的相对表达。我们观察到，通过DNR选择的细胞显然比通过VCR选择的细胞产生更高的能量需求。即使在将DNR从FEPS培养物中撤出一个月后，转录因子基因（nrf2、hif-1α和oct4）的高表达水平仍保持不变。这些结果共同表明，DNR选择的细胞具有更强的能力来表达与抗氧化防御系统相关的主要转录因子以及与MDR表型相关的主要外排泵（ABCB1）。考虑到肿瘤细胞的抗氧化能力与对多种药物的耐药性密切相关，显然内源性抗氧化分子可能成为开发新型抗癌药物的靶点。
