Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan;
Department of Clinical Oncology, Yamagata Prefectural Shinjo Hospital, Yamagata, Japan.
Anticancer Res. 2024 Sep;44(9):3875-3883. doi: 10.21873/anticanres.17214.
BACKGROUND/AIM: Glioblastoma is the most aggressive form of brain tumor and has a dismal prognosis; therefore, novel therapeutic approaches based on the mechanisms underlying its aggressive nature are urgently required. A growing body of evidence suggests that neurotransmitters play a key role in modulating the biology of glioblastoma; however, the role of melanocortins remains unclear.
The effects of bremelanotide, a melanocortin receptor agonist, alone or in combination with chemotherapeutic agents, on survivin expression and cell viability were investigated in human glioblastoma cell lines.
Bremelanotide reduced survivin expression and induced cell death in glioblastoma cells at concentrations that were not toxic to normal human cells, and both of these effects were canceled in the presence of an antagonist of melanocortin receptors 3 and 4. Bremelanotide-induced cell death was prevented by the forced over-expression of survivin in glioblastoma cells, suggesting that bremelanotide induces glioblastoma cell death by inhibiting the expression of survivin. Bremelanotide also promoted cell death induced by chemotherapeutic agents, such as temozolomide and osimertinib.
The present results identified melanocortin receptors 3 and 4 as novel and viable therapeutic targets for glioblastoma. Activation of these receptors by bremelanotide may inhibit the expression of survivin, thereby sensitizing glioblastoma cells to cell death.
背景/目的：胶质母细胞瘤是最具侵袭性的脑肿瘤，预后极差；因此，迫切需要基于其侵袭性机制的新型治疗方法。越来越多的证据表明，神经递质在调节胶质母细胞瘤的生物学特性方面发挥着关键作用；然而，黑素细胞刺激素的作用仍不清楚。
研究了黑素细胞刺激素受体激动剂布雷默龙单独或与化疗药物联合使用对人胶质母细胞瘤细胞系中生存素表达和细胞活力的影响。
布雷默龙在对正常人细胞无毒的浓度下降低了生存素的表达并诱导了胶质母细胞瘤细胞死亡，而这两种作用在存在黑素细胞刺激素受体 3 和 4 的拮抗剂时都被取消了。在胶质母细胞瘤细胞中强制过表达生存素可阻止布雷默龙诱导的细胞死亡，表明布雷默龙通过抑制生存素的表达诱导胶质母细胞瘤细胞死亡。布雷默龙还促进了化疗药物如替莫唑胺和奥希替尼诱导的细胞死亡。
本研究结果确定了黑素细胞刺激素受体 3 和 4 是胶质母细胞瘤的新型可行治疗靶点。布雷默龙激活这些受体可能抑制生存素的表达，从而使胶质母细胞瘤细胞对细胞死亡敏感。
