Research Laboratory in Applied Metabolic Engineering, Department of Chemical Engineering, Polytechnique Montréal, Centre-Ville Station, P.O. Box 6079, Montréal, QC H3C 3A7, Canada.
Assistance Publique des Hôpitaux de Paris, Avenue Victoria, 75003 Paris, France.
Int J Mol Sci. 2024 Oct 13;25(20):11005. doi: 10.3390/ijms252011005.
Ovarian cancer presents a dire prognosis and high mortality rates, necessitating the exploration of alternative therapeutic avenues, particularly in the face of platinum-based chemotherapy resistance. Conventional treatments often overlook the metabolic implications of cancer, but recent research has highlighted the pivotal role of mitochondria in cancer pathogenesis and drug resistance. This study delves into the metabolic landscape of ovarian cancer treatment, focusing on modulating mitochondrial activity using methylene blue (MB). Investigating two epithelial ovarian cancer (EOC) cell lines, OV1369-R2 and OV1946, exhibiting disparate responses to carboplatin, we sought to identify metabolic nodes, especially those linked to mitochondrial dysfunction, contributing to chemo-resistance. Utilizing ARPE-19, a normal retinal epithelial cell line, as a control model, our study reveals MB's distinct cellular uptake, with ARPE-19 absorbing 5 to 7 times more MB than OV1946 and OV1369-R2. Treatment with 50 µM MB (MB-50) effectively curtailed the proliferation of both ovarian cancer cell lines. Furthermore, MB-50 exhibited the ability to quell glutaminolysis and the Warburg effect in cancer cell cultures. Regarding mitochondrial energetics, MB-50 spurred oxygen consumption, disrupted glycolytic pathways, and induced ATP depletion in the chemo-sensitive OV1946 cell line. These findings highlight the potential of long-term MB exposure as a strategy to improve the chemotherapeutic response in ovarian cancer cells. The ability of MB to stimulate oxygen consumption and enhance mitochondrial activity positions it as a promising candidate for ovarian cancer therapy, shedding light on the metabolic pressures exerted on mitochondria and their modulation by MB, thus contributing to a deeper understanding of mitochondrial dysregulation and the metabolic underpinnings of cancer cell proliferation.
卵巢癌预后较差，死亡率较高，因此需要探索其他治疗方法，特别是在面对铂类化疗耐药时。传统治疗方法通常忽略了癌症的代谢影响，但最近的研究强调了线粒体在癌症发病机制和耐药性中的关键作用。本研究深入探讨了卵巢癌治疗的代谢景观，重点研究了使用亚甲蓝（MB）调节线粒体活性。研究了两种上皮性卵巢癌（EOC）细胞系，OV1369-R2 和 OV1946，它们对卡铂的反应不同，我们试图确定代谢节点，特别是与线粒体功能障碍相关的代谢节点，这些节点导致化疗耐药。利用 ARPE-19（一种正常的视网膜上皮细胞系）作为对照模型，我们的研究揭示了 MB 的独特细胞摄取，ARPE-19 吸收的 MB 比 OV1946 和 OV1369-R2 多 5 到 7 倍。用 50µM MB（MB-50）处理可有效抑制两种卵巢癌细胞系的增殖。此外，MB-50 能够抑制癌细胞培养物中的谷氨酰胺分解和瓦博格效应。关于线粒体能量学，MB-50 刺激耗氧量，破坏糖酵解途径，并在化疗敏感的 OV1946 细胞系中诱导 ATP 耗竭。这些发现强调了长期暴露于 MB 的潜在可能性，作为改善卵巢癌细胞化疗反应的策略。MB 刺激耗氧量和增强线粒体活性的能力使其成为卵巢癌治疗的有前途的候选药物，这突显了对线粒体施加的代谢压力及其被 MB 调节的情况，从而更深入地了解线粒体失调和癌细胞增殖的代谢基础。
