Honc Ondrej, Novotny Jiri
Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic.
Cancers (Basel). 2023 Jul 11;15(14):3567. doi: 10.3390/cancers15143567.
Methadone is commonly used as an alternative to morphine in patients with pain associated with glioblastoma and other cancers. Although concomitant administration of methadone and cytostatics is relatively common, the effect of methadone on the efficacy of cytostatic drugs has not been well studied until recently. Moreover, the mechanism behind the effect of methadone on temozolomide efficacy has not been investigated in previous studies, or this effect has been automatically attributed to opioid receptors. Our findings indicate that methadone potentiates the effect of temozolomide on rat C6 glioblastoma cells and on human U251 and T98G glioblastoma cells and increases cell mortality by approximately 50% via a mechanism of action independent of opioid receptors. Our data suggest that methadone acts by affecting mitochondrial potential, the level of oxidative stress, intracellular Ca concentration and possibly intracellular ATP levels. Significant effects were also observed on DNA integrity and on cleavage and expression of the DNA repair protein PARP-1. None of these effects were attributed to the activation of opioid receptors and Toll-like receptor 4. Our results provide an alternative perspective on the mechanism of action of methadone in combination with temozolomide and a potential strategy for the treatment of glioblastoma cell resistance to temozolomide.
美沙酮通常被用作患有胶质母细胞瘤和其他癌症相关疼痛患者的吗啡替代药物。尽管美沙酮与细胞抑制剂联合给药相对常见，但直到最近，美沙酮对细胞抑制药物疗效的影响尚未得到充分研究。此外，美沙酮对替莫唑胺疗效影响背后的机制在以往研究中尚未被探究，或者这种影响被自动归因于阿片受体。我们的研究结果表明，美沙酮可增强替莫唑胺对大鼠C6胶质母细胞瘤细胞以及人U251和T98G胶质母细胞瘤细胞的作用，并通过一种独立于阿片受体的作用机制使细胞死亡率增加约50%。我们的数据表明，美沙酮通过影响线粒体电位、氧化应激水平、细胞内钙浓度以及可能的细胞内ATP水平发挥作用。在DNA完整性以及DNA修复蛋白PARP-1的切割和表达方面也观察到了显著影响。这些影响均未归因于阿片受体和Toll样受体4的激活。我们的结果为美沙酮与替莫唑胺联合作用机制提供了另一种视角，并为治疗胶质母细胞瘤细胞对替莫唑胺的耐药性提供了一种潜在策略。
