Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
Faculty of Medical Technology, Mahidol University, Thailand.
Oxid Med Cell Longev. 2022 May 9;2022:9664636. doi: 10.1155/2022/9664636. eCollection 2022.
We have employed a redox-active MnP (MnTnBuOE-2-PyP, Mn(III) meso-tetrakis (N-n-butoxyethylpyridinium-2-yl) porphyrin) frequently identified as superoxide dismutase mimic or BMX-001, to explore the redox status of normal ovarian cell in relation to two ovarian cancer cell lines: OV90 human serous ovarian cancer cell and chemotherapy-resistant OV90 cell (OVCD). We identified that OVCD cells are under oxidative stress due to high hydrogen peroxide (HO) levels and low glutathione peroxidase and thioredoxin 1. Furthermore, OVCD cells have increased glycolysis activity and mitochondrial respiration when compared to immortalized ovarian cells (hTER7) and parental cancer cells (OV90). Our goal was to study how ovarian cell growth depends upon the redox state of the cell; hence, we used MnP (BMX-001), a redox-active MnSOD mimetic, as a molecular tool to alter ovarian cancer redox state. Interestingly, OVCD cells preferentially uptake MnP relative to OV90 cells which led to increased inhibition of cell growth, glycolytic activity, OXPHOS, and ATP, in OVCD cells. These effects were further increased when MnP was combined with carboplatin. The effects were discussed with regard to the elevation in HO levels, increased oxidative stress, and reduced Nrf2 levels and its downstream targets when cells were exposed to either MnP or MnP/carboplatin. It is significant to emphasize that MnP protects normal ovarian cell line, hTER7, against carboplatin toxicity. Our data demonstrate that the addition of MnP-based redox-active drugs may be used (via increasing excessively the oxidative stress of serous ovarian cancer cells) to improve cancer patients' chemotherapy outcomes, which develop resistance to platinum-based drugs.
我们使用了一种氧化还原活性的 MnP（MnTnBuOE-2-PyP，Mn(III) 中四（N-正丁氧基乙基吡啶-2-基）卟啉），它通常被认为是超氧化物歧化酶模拟物或 BMX-001，以研究正常卵巢细胞的氧化还原状态与两种卵巢癌细胞系：OV90 人浆液性卵巢癌细胞和化疗耐药 OV90 细胞（OVCD）的关系。我们发现 OVCD 细胞由于高水平的过氧化氢（HO）和低谷胱甘肽过氧化物酶和硫氧还蛋白 1 而处于氧化应激状态。此外，与永生化卵巢细胞（hTER7）和亲本癌细胞（OV90）相比，OVCD 细胞的糖酵解活性和线粒体呼吸增加。我们的目标是研究卵巢细胞生长如何依赖于细胞的氧化还原状态；因此，我们使用了 MnP（BMX-001），一种氧化还原活性的 MnSOD 模拟物，作为改变卵巢癌细胞氧化还原状态的分子工具。有趣的是，与 OV90 细胞相比，OVCD 细胞优先摄取 MnP，导致 OVCD 细胞的细胞生长、糖酵解活性、OXPHOS 和 ATP 抑制增加。当 MnP 与卡铂联合使用时，这些效果进一步增强。当细胞暴露于 MnP 或 MnP/卡铂时，讨论了这些效应与 HO 水平升高、氧化应激增加以及 Nrf2 水平和其下游靶标降低有关。值得强调的是，MnP 可保护正常卵巢细胞系 hTER7 免受卡铂毒性的影响。我们的数据表明，添加基于 MnP 的氧化还原活性药物（通过过度增加浆液性卵巢癌细胞的氧化应激）可能用于改善对铂类药物产生耐药性的癌症患者的化疗效果。
