Functional inhibition of BCL2 is needed to increase the susceptibility to apoptosis to SMO inhibitors in diffuse large B-cell lymphoma of germinal center subtype.
Functional inhibition of BCL2 is needed to increase the susceptibility to apoptosis to SMO inhibitors in diffuse large B-cell lymphoma of germinal center subtype.
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DOI：
10.1007/s00277-013-1684-6
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发表时间：
2013-06
影响因子：
3.5
通讯作者：
Vega, Francisco
中科院分区：
文献类型：
--
作者：
Kunkalla, Kranthi;Liu, Yadong;Qu, Changju;Leventaki, Vasiliki;Agarwal, Nitin K.;Singh, Rajesh R.;Vega, Francisco
关键词：
以前，我们已经证明，抑制Hedgehog途径诱导主要是活化B细胞（ABC）型弥漫性大B细胞淋巴瘤（DLBCL）细胞系的细胞凋亡，但主要是在生发中心（GC）的细胞周期阻滞。在此，我们探索了使用SMO抑制剂HhAntag（Genentech Inc）与BH 3模拟物ABT-737（Abbott Laboratories）的组合在5种GC型DLBCL细胞中克服对SMO抑制剂的凋亡抗性的可能性。作为对照，我们使用了2例ABC型DLBCL（OCI-LY 10和OCI-LY 3）。用增加浓度的HhAntag与低剂量（等于或小于IC 20）的ABT-737进行组合处理。MTT法用于检测细胞活力的变化，Annexin-V和PARP 1裂解法用于检测细胞凋亡。在GC DLBCL细胞系中，低剂量的ABT-737与增加浓度的HhAntag组合导致与单独使用SMO抑制剂的处理相比凋亡显著增加。我们的结论是，在GC DLBCL细胞系中，与ABC型相反，通常需要BCL 2家族成员的功能抑制来克服对SMO抑制剂的凋亡抗性。这些发现为探索SMO和BCL 2抑制剂作为GC型DLBCL的辅助治疗提供了理论基础。
Previously, we have demonstrated that inhibition of Hedgehog pathway induces predominantly apoptosis in diffuse large B-cell lymphoma (DLBCL) cell lines of activated B-cell (ABC) type but predominantly cell cycle arrest in those of germinal center (GC). Here, we explored the possibility of overcoming the resistance to apoptosis to SMO inhibitors in 5 DLBCL cells of GC type using the combination of the SMO inhibitor HhAntag (Genentech Inc) with the BH3 mimetic ABT-737 (Abbott Laboratories). As controls we have used 2 DLBCL of ABC type (OCI-LY10 and OCI-LY3). Combinatorial treatments were performed with increasing concentrations of the HhAntag with low-doses (equal or less than the IC20) of ABT-737. MTT assays were used to detect changes in cell viability and Annexin-V and PARP1 cleavage assays were used to detect apoptosis. Combining low-doses of ABT-737 with increasing concentrations of HhAntag in GC DLBCL cell lines resulted in significantly increase of apoptosis in comparison to treatments with the SMO inhibitor alone. We concluded that in GC DLBCL cell lines, in contrast to those of ABC type, functional inhibition of BCL2 family members is usually needed to overcome the resistance to apoptosis to SMO inhibitors. These findings provide a rationale to explore the use of SMO and BCL2 inhibitors as adjuvant therapy for treatment of DLBCL of GC type.
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