Rudbeck Laboratory, Department of Radiation, Oncology and Radiation Science, Section of Oncology, Uppsala University, Dag Hammarskjölds väg 20, Uppsala, Sweden.
Cancer Chemother Pharmacol. 2013 Aug;72(2):329-40. doi: 10.1007/s00280-013-2197-7. Epub 2013 Jun 5.
The current treatment strategies for glioblastoma have limited health and survival benefits for the patients. A common obstacle in the treatment is chemoresistance. A possible strategy to evade this problem may be to combine chemotherapeutic drugs with agents inhibiting resistance mechanisms. The aim with this study was to identify molecular pathways influencing drug resistance in glioblastoma-derived cells and to evaluate the potential of pharmacological interference with these pathways to identify synergistic drug combinations.
Global gene expressions and drug sensitivities to three chemotherapeutic drugs (imatinib, camptothecin and temozolomide) were measured in six human glioblastoma-derived cell lines. Gene expressions that correlated to drug sensitivity or resistance were identified and mapped to specific pathways. Selective inhibitors of these pathways were identified. The effects of six combinations of inhibitors and chemotherapeutic drugs were evaluated in glioblastoma-derived cell lines. Drug combinations with synergistic effects were also evaluated in non-cancerous epithelial cells.
Four drug combinations had synergistic effects in at least one of the tested glioblastoma-derived cell lines; camptothecin combined with gefitinib (epidermal growth factor receptor inhibitor) or NSC 23766 (ras-related C3 botulinum toxin substrate 1 inhibitor) and imatinib combined with DAPT (Notch signaling inhibitor) or NSC 23766. Of these, imatinib combined with DAPT or NSC 23766 did not have synergistic effects in non-cancerous epithelial cells. Two drug combinations had at least additive effects in one of the tested glioblastoma-derived cell lines; temozolomide combined with gefitinib or PF-573228 (focal adhesion kinase inhibitor).
Four synergistic and two at least additive drug combinations were identified in glioblastoma-derived cells. Pathways targeted by these drug combinations may serve as targets for future drug development with the potential to increase efficacy of currently used/evaluated chemotherapy.
胶质母细胞瘤的当前治疗策略对患者的健康和生存获益有限。治疗中的一个常见障碍是化疗耐药。规避这个问题的一种可能策略是将化疗药物与抑制耐药机制的药物联合使用。本研究的目的是确定影响胶质母细胞瘤衍生细胞中药物耐药的分子途径，并评估药理学干扰这些途径以确定协同药物组合的潜力。
在六种人胶质母细胞瘤衍生细胞系中测量了三种化疗药物（伊马替尼、喜树碱和替莫唑胺）的全基因表达和药物敏感性。鉴定与药物敏感性或耐药性相关的基因表达，并将其映射到特定途径。鉴定这些途径的选择性抑制剂。评估六种抑制剂和化疗药物组合在胶质母细胞瘤衍生细胞系中的作用。还评估了在非癌性上皮细胞中具有协同作用的药物组合。
在至少一种测试的胶质母细胞瘤衍生细胞系中，四种药物组合具有协同作用；喜树碱联合吉非替尼（表皮生长因子受体抑制剂）或 NSC 23766（ras 相关 C3 肉毒杆菌毒素底物 1 抑制剂）和伊马替尼联合 DAPT（Notch 信号通路抑制剂）或 NSC 23766。其中，伊马替尼联合 DAPT 或 NSC 23766在非癌性上皮细胞中没有协同作用。两种药物组合在至少一种测试的胶质母细胞瘤衍生细胞系中具有至少相加作用；替莫唑胺联合吉非替尼或 PF-573228（粘着斑激酶抑制剂）。
在胶质母细胞瘤衍生细胞中鉴定出四种协同和两种至少相加的药物组合。这些药物组合靶向的途径可能作为未来药物开发的靶点，有可能提高目前使用/评估的化疗的疗效。
