Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological Sciences, University of Milan - Università degli Studi di Milano, Milan, Italy.
Adv Exp Med Biol. 2020;1202:13-33. doi: 10.1007/978-3-030-30651-9_2.
Purines and pyrimidines are fundamental signaling molecules in controlling the survival and proliferation of astrocytes, as well as in mediating cell-to-cell communication between glial cells and neurons in the healthy brain. The malignant transformation of astrocytes towards progressively more aggressive brain tumours (from astrocytoma to anaplastic glioblastoma) leads to modifications in both the survival and cell death pathways which overall confer a growth advantage to malignant cells and resistance to many cytotoxic stimuli. It has been demonstrated, however, that, in astrocytomas, several purinergic (in particular adenosinergic) pathways controlling cell survival and death are still effective and, in some cases, even enhanced, providing invaluable targets for purine-based chemotherapy, that still represents an appropriate pharmacological approach to brain tumours. In this chapter, the current knowledge on both receptor-mediated and receptor-independent adenosine pathways in astrocytomas will be reviewed, with a particular emphasis on the most promising targets which could be translated from in vitro studies to in vivo pharmacology. Additionally, we have included new original data from our laboratory demonstrating a key involvement of MAP kinases in the cytostastic and cytotoxic effects exerted by an adenosine analogue, 2-CdA, which with the name of Cladribine is already clinically utilized in haematological malignancies. Here we show that 2-CdA can activate multiple intracellular pathways leading to cell cycle block and cell death by apoptosis of a human astrocytoma cell line that bears several pro-survival genetic mutations. Although in vivo data are still lacking, our results suggest that adenosine analogues could therefore be exploited to overcome resistance to chemotherapy of brain tumours.
嘌呤和嘧啶是控制星形胶质细胞存活和增殖的基本信号分子，也是介导胶质细胞和神经元之间细胞间通讯的重要分子。星形胶质细胞向侵袭性更强的脑肿瘤（从星形细胞瘤到间变性神经胶质瘤）的恶性转化导致了存活和细胞死亡途径的改变，这些改变总体上赋予了恶性细胞生长优势，并对许多细胞毒性刺激产生了抗性。然而，已经证明，在星形细胞瘤中，几种嘌呤能（特别是腺苷能）途径控制细胞的存活和死亡仍然有效，在某些情况下甚至增强，为基于嘌呤的化疗提供了宝贵的靶点，这仍然是治疗脑肿瘤的一种合适的药理学方法。在本章中，将综述星形胶质细胞瘤中受体介导和受体非依赖的腺苷途径的最新知识，特别强调最有前途的靶点，这些靶点可以从体外研究转化为体内药理学。此外，我们还包括了我们实验室的新原始数据，证明 MAP 激酶在由腺苷类似物 2-CdA 引起的星形细胞瘤细胞的细胞毒性和细胞毒性作用中起着关键作用，该类似物以克拉屈滨的名称已在血液恶性肿瘤中临床应用。在这里，我们证明 2-CdA 可以激活多种细胞内途径，导致细胞周期阻滞和细胞凋亡，而人类星形细胞瘤细胞系具有多种抗凋亡的遗传突变。尽管体内数据仍然缺乏，但我们的结果表明，因此，腺苷类似物可以被用来克服脑肿瘤对化疗的耐药性。
