Chen Yixiang, Germano Sandra, Clements Chris, Samuel Jesvin, Shelmani Ghalia, Jayne Sandrine, Dyer Martin J S, Macip Salvador
Mechanisms of Cancer and Ageing Laboratory, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, UK.
Br J Haematol. 2016 Nov;175(4):641-651. doi: 10.1111/bjh.14285. Epub 2016 Jul 29.
Dinaciclib is a cyclin-dependent kinase inhibitor with clinical potential in different cancers, including chronic lymphocytic leukaemia (CLL). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT3, NF-κB, p38, PI3K/AKT and RAF/MEK/ERK. Dinaciclib was also able to block the expression of anti-apoptotic proteins of the BCL2 family such as MCL1 and BCL-xL (also termed BCL2L1). Finally, we showed that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and the BCL2 inhibitor ABT-199, two drugs with known effects on CLL. Taken together, our data show that dinaciclib targets multiple pro-survival signalling pathways in CLL, which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of cyclin-dependent kinase inhibitors in CLL in combination with other relevant targeted therapies.
地西他滨是一种细胞周期蛋白依赖性激酶抑制剂，在包括慢性淋巴细胞白血病（CLL）在内的不同癌症中具有临床应用潜力。为了更好地理解其细胞毒性作用，我们对其对CLL细胞存活至关重要的信号通路的影响进行了表征。我们发现地西他滨通过激活半胱天冬酶8和9诱导细胞凋亡，这与模拟增殖中心环境的细胞因子的存在或IGVH突变状态无关。此外，用地西他滨治疗导致通常在受刺激的CLL细胞中激活的致癌通路受到抑制，如STAT3、NF-κB、p38、PI3K/AKT和RAF/MEK/ERK。地西他滨还能够阻断BCL2家族抗凋亡蛋白如MCL1和BCL-xL（也称为BCL2L1）的表达。最后，我们表明低浓度的地西他滨增强了细胞对依鲁替尼和BCL2抑制剂ABT-199的敏感性，这两种药物对CLL有已知作用。综上所述，我们的数据表明地西他滨靶向CLL中的多种促存活信号通路，这为其有效诱导细胞凋亡提供了机制解释。它们还支持细胞周期蛋白依赖性激酶抑制剂在CLL中与其他相关靶向疗法联合的治疗应用。
