Marcelino Helena, Carvalho Tiago M A, Tomás Joana, Teles Francisca I, Honório Ana C, Rosa Carolina B, Costa Ana R, Costa Bruno M, Santos Cecília R A, Sebastião Ana M, Cascalheira José F
CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal; Department of Chemistry, University of Beira Interior, Covilhã, Portugal.
CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal.
Neuroscience. 2021 Jul 15;467:122-133. doi: 10.1016/j.neuroscience.2021.05.019. Epub 2021 May 24.
Glioblastoma (GBM) is the most common brain primary tumour. Hypoxic regions in GBM are associated to tumour growth. Adenosine accumulates in hypoxic regions and can affect cell proliferation and survival. However, how proliferating GBM cells respond/adapt to increased adenosine levels compared to human astrocytes (HA) is not clarified and was addressed in the present work. GBM cell lines and HA were treated for 3 days with test drugs. Thirty Adenosine (30 µM) caused a 43% ± 5% (P < 0.05) reduction of cell proliferation/viability in HA, through an adenosine receptor-independent mechanism, but had no effect in GBM cell lines U87MG, U373MG and SNB19. Contrastingly, inhibition of adenosine phosphorylation (using the adenosine kinase (ADK) inhibitor 5-iodotubercidin (ITU) (25 µM)), produced a strong and similar decrease on cell proliferation in both HA and GBM cells. The effect of adenosine on HA proliferation/viability was potentiated by 100 µM-homocysteine. Combined application of 30 µM-adenosine and 100 µM-homocysteine reduced the cell proliferation/viability in all three GBM cell lines, but this reduction was much lower than that observed in HA. Adenosine alone did not induce cell death, assessed by lactate dehydrogenase (LDH) release, both in HA and GBM cells, but potentiated the cytotoxic effect of homocysteine in HA and in U87MG and U373MG cells. Results show a strong attenuation of adenosine anti-proliferative effect in GBM cells compared to HA, probably resulting from increased adenosine elimination by ADK, suggesting a proliferative-prone adaptation of tumour cells to increased adenosine levels.
胶质母细胞瘤（GBM）是最常见的脑原发性肿瘤。GBM中的缺氧区域与肿瘤生长相关。腺苷在缺氧区域积聚，可影响细胞增殖和存活。然而，与人类星形胶质细胞（HA）相比，增殖性GBM细胞如何响应/适应腺苷水平升高尚不清楚，本研究对此进行了探讨。用受试药物处理GBM细胞系和HA 3天。30 μM腺苷通过非腺苷受体依赖性机制使HA中的细胞增殖/活力降低43%±5%（P<0.05），但对GBM细胞系U87MG、U373MG和SNB19无影响。相反，抑制腺苷磷酸化（使用腺苷激酶（ADK）抑制剂5-碘尿苷（ITU）（25 μM））可使HA和GBM细胞中的细胞增殖显著且相似地降低。100 μM同型半胱氨酸可增强腺苷对HA增殖/活力的影响。联合应用30 μM腺苷和100 μM同型半胱氨酸可降低所有三种GBM细胞系中的细胞增殖/活力，但这种降低远低于HA中的观察结果。单独使用腺苷在HA和GBM细胞中均未通过乳酸脱氢酶（LDH）释放评估诱导细胞死亡，但可增强同型半胱氨酸在HA以及U87MG和U373MG细胞中的细胞毒性作用。结果表明，与HA相比，GBM细胞中腺苷的抗增殖作用明显减弱，这可能是由于ADK增加了腺苷的消除，提示肿瘤细胞对腺苷水平升高具有易于增殖的适应性。
