Balça-Silva Joana, Matias Diana, do Carmo Anália, Girão Henrique, Moura-Neto Vivaldo, Sarmento-Ribeiro Ana Bela, Lopes Maria Celeste
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Instituto Estadual do Cérebro Paulo Niemeyer (IECPN), Rio de Janeiro, Brazil.
Biochim Biophys Acta. 2015 Apr;1850(4):722-32. doi: 10.1016/j.bbagen.2014.12.022. Epub 2014 Dec 29.
Glioblastoma (GBM) is a highly proliferative, angiogenic grade IV astrocytoma that develops resistance to the alkylating agents used in chemotherapy, such as temozolomide (TMZ), which is considered the gold standard. The mean survival time for GBM patients is approximately 12 months, increasing to 14.6 months after TMZ treatment. The resistance of GBM to chemotherapy seems to be associated to genetic alterations and to the constitutive activation of several signaling pathways. Therefore, the combination of different drugs with different mechanisms of action may contribute to circumvent the chemoresistance of glioma cells. Here we describe the potential synergistic behavior of the therapeutic combination of tamoxifen (TMX), a known inhibitor of PKC, and TMZ in GBM.
We used two GBM cell lines incubated in absence and presence of TMX and/or TMZ and measured cell viability, proliferation, apoptosis, cell cycle, migration ability, cytoskeletal organization and the phosphorylated amount of the p-PKC-pan.
The combination of low doses of TMX with increasing doses of TMZ shows an increased antiproliferative and apoptotic effect compared to the effect with TMX alone.
The combination of TMX and TMZ seems to potentiate the effect of each other. These alterations seem to be associated to a decrease in the phosphorylation status of PKC.
We emphasize that TMX is an inhibitor of the p-PKC-pan and that these combination is more effective in the reduction of proliferation and in the increase of apoptosis than each drug alone, which presents a new therapeutic strategy in GBM treatment.
胶质母细胞瘤（GBM）是一种增殖性高、具有血管生成能力的IV级星形细胞瘤，对化疗中使用的烷化剂产生耐药性，如被视为金标准的替莫唑胺（TMZ）。GBM患者的平均生存时间约为12个月，TMZ治疗后可增至14.6个月。GBM对化疗的耐药性似乎与基因改变以及多种信号通路的组成性激活有关。因此，联合使用具有不同作用机制的不同药物可能有助于克服胶质瘤细胞的化疗耐药性。在此，我们描述了已知的蛋白激酶C（PKC）抑制剂他莫昔芬（TMX）与TMZ联合治疗GBM的潜在协同作用。
我们使用了两种GBM细胞系，分别在不存在和存在TMX和/或TMZ的情况下进行培养，并测量细胞活力、增殖、凋亡、细胞周期、迁移能力、细胞骨架组织以及p-PKC-pan的磷酸化水平。
与单独使用TMX相比，低剂量TMX与递增剂量TMZ联合使用显示出更强的抗增殖和凋亡作用。
TMX与TMZ联合使用似乎能增强彼此的效果。这些改变似乎与PKC磷酸化状态的降低有关。
我们强调TMX是p-PKC-pan的抑制剂，并且这种联合用药在减少增殖和增加凋亡方面比单独使用每种药物更有效，这为GBM治疗提供了一种新的治疗策略。
