Connelly Katelyn E, Martin Emily C, Dykhuizen Emily C
Purdue University, West Lafayette, IN.
Jefferson High School, Lafayette, IN.
Yale J Biol Med. 2016 Dec 23;89(4):431-440. eCollection 2016 Dec.
Glioblastoma multiforme (GBM) lacks effective therapeutic options leaving patients with a survival time of approximately one year. Recently, the alteration of chromatin modulators has been implicated in the pathogenesis and chemoresistance of numerous cancers; in particular, the Polycomb Group Proteins have been shown to play a role in glioblastoma progression and maintenance [1-5]. In this study, we aimed to identify drug combinations that decrease GBM cell viability by combining small molecule inhibitors against the Polycomb family with two standard chemotherapies. We identified dual inhibition of the CBX chromodomain with doxorubicin as a novel therapeutic strategy. While treatment with chromodomain inhibitor is non-toxic to cells alone, it dramatically increased the toxicity of standard chemotherapy drugs. We further validated an increase in DNA damage resulting in a G2/M block and subsequent apoptosis using the dual inhibitor treatment.
多形性胶质母细胞瘤（GBM）缺乏有效的治疗方案，患者的生存时间约为一年。最近，染色质调节剂的改变与多种癌症的发病机制和化疗耐药性有关；特别是，多梳蛋白家族已被证明在胶质母细胞瘤的进展和维持中发挥作用[1-5]。在本研究中，我们旨在通过将针对多梳家族的小分子抑制剂与两种标准化疗药物联合使用，来确定能降低GBM细胞活力的药物组合。我们确定了用阿霉素双重抑制CBX染色质结构域是一种新的治疗策略。虽然单独使用染色质结构域抑制剂对细胞无毒，但它显著增加了标准化疗药物的毒性。我们进一步验证了使用双重抑制剂治疗会增加DNA损伤，导致G2/M期阻滞并随后引发细胞凋亡。
