Oxidative stress role on metformin process of dacarbazine (DTIC) inducing resistance of B16F10 melanoma murine cells are investigated. To induce resistance to DTIC, murine melanoma cells were exposed to increasing concentrations of dacarabazine (DTIC-res group). Metformin was administered before and during the induction of resistance to DTIC (MET-DTIC). The oxidative stress parameters of the DTIC-res group showed increased levels of malondialdehyde (MDA), thiol, and reduced nuclear p53, 8-hydroxy-2ʹ-deoxyguanosine (8-OH-DG), nuclear factor kappa B (NF-ĸB), and Nrf2. In presence of metformin in the resistant induction process to DTIC, (MET-DTIC) cells had increased antioxidant thiols, MDA, nuclear p53, 8-OH-DG, Nrf2, and reducing NF-ĸB, weakening the DTIC-resistant phenotype. The exclusive administration of metformin (MET group) also induced the cellular resistance to DTIC. The MET group presented high levels of total thiols, MDA, and reduced percentage of nuclear p53. It also presented reduced nuclear 8-OH-DG, NF-ĸB, and Nrf2 when compared with the control. Oxidative stress and the studied biomarkers seem to be part of the alterations evidenced in DTIC-resistant B16F10 cells. In addition, metformin administration is able to play a dual role according to the experimental protocol, preventing or inducing a DTIC-resistant phenotype. These findings should help future research with the aim of investigating DTIC resistance in melanoma.

中文翻译：

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二甲双胍预处理可降低对达卡巴嗪的作用并抑制黑色素瘤细胞耐药性

研究了氧化应激对达卡巴嗪 (DTIC) 诱导 B16F10 黑色素瘤小鼠细胞抗性的二甲双胍过程的作用。为了诱导对 DTIC 的抗性，将鼠黑色素瘤细胞暴露于浓度增加的达卡拉巴嗪（DTIC-res 组）。在诱导对 DTIC (MET-DTIC) 产生抗性之前和期间给予二甲双胍。DTIC-res 组的氧化应激参数显示丙二醛 (MDA)、硫醇水平升高，核 p53、8-羟基-2′-脱氧鸟苷 (8-OH-DG)、核因子 kappa B (NF-ĸB) 减少, 和 Nrf2。在二甲双胍对 DTIC 的抗性诱导过程中，(MET-DTIC) 细胞增加了抗氧化硫醇、MDA、核 p53、8-OH-DG、Nrf2，并减少了 NF-ĸB，削弱了 DTIC 抗性表型。二甲双胍（MET组）的独家给药也诱导了细胞对DTIC的抗性。MET 组呈现高水平的总硫醇、MDA 和降低的核 p53 百分比。与对照相比，它还呈现出减少的核 8-OH-DG、NF-ĸB 和 Nrf2。氧化应激和研究的生物标志物似乎是 DTIC 抗性 B16F10 细胞中所证明的改变的一部分。此外，根据实验方案，二甲双胍给药能够发挥双重作用，防止或诱导 DTIC 抗性表型。这些发现应该有助于未来的研究，目的是调查黑色素瘤的 DTIC 耐药性。