Whittaker Shane, Madani Daniel, Joshi Swapna, Chung Sylvia A, Johns Terrance, Day Bryan, Khasraw Mustafa, McDonald Kerrie L
Cure Brain Cancer Foundation Biomarkers and Translational Research Group, Prince of Wales Clinical School, University of New South Wales Sydney, Sydney, NSW, Australia.
Oncogenic Signalling Laboratory, Hudson Institute of Medical Research, Centre for Cancer Research, Melbourne, VIC, Australia.
Cell Death Discov. 2017 Jul 3;3:17033. doi: 10.1038/cddiscovery.2017.33. eCollection 2017.
The cyclin-dependent kinase inhibitor, palbociclib has shown compelling efficacy in breast cancer patients. Several pre-clinical studies of glioblastoma (GBM) have also shown palbociclib to be efficacious. In this study, we investigated palbociclib in combination with radiation therapy (RT) for treating GBM. We tested palbociclib (with and without RT) on four patient-derived cell lines (PDCLs; RB1 retained; CDKN2A loss). We investigated the impact of therapy on the cell cycle and apoptosis using flow cytometry, . Balb/c nude mice were intracranially injected with the PDCL, GBM-L1 and treated orally with palbociclib (with and without RT). Overall survival was measured. Palbociclib treatment resulted in a significant increase in the percentage of cells in the G1 cell cycle phase. Apoptotic cell death, measured by Annexin V was induced. Palbociclib combined with RT acted synergistically with the significant impediment of colony formation. The oral treatment of mice with palbociclib did not show any significant survival advantage when compared to control mice, however when combined with RT, a survival advantage of 8 days was observed. Our results support the use of palbociclib as an adjuvant treatment to RT and warrant translation to the clinic.
细胞周期蛋白依赖性激酶抑制剂帕博西尼在乳腺癌患者中已显示出令人信服的疗效。多项胶质母细胞瘤（GBM）的临床前研究也表明帕博西尼具有疗效。在本研究中，我们研究了帕博西尼联合放射治疗（RT）用于治疗GBM的效果。我们在四种患者来源的细胞系（PDCLs；RB1保留；CDKN2A缺失）上测试了帕博西尼（有或无RT）。我们使用流式细胞术研究了治疗对细胞周期和细胞凋亡的影响。将Balb/c裸鼠颅内注射PDCL、GBM-L1，并口服帕博西尼（有或无RT）。测量总体生存期。帕博西尼治疗导致G1细胞周期阶段的细胞百分比显著增加。通过膜联蛋白V检测诱导了凋亡细胞死亡。帕博西尼联合RT与显著阻碍集落形成具有协同作用。与对照小鼠相比，口服帕博西尼治疗的小鼠未显示出任何显著的生存优势，然而，当与RT联合使用时，观察到有8天的生存优势。我们的结果支持将帕博西尼用作RT的辅助治疗，并值得向临床转化。
