The novel proteasome inhibitor carfilzomib induces cell cycle arrest, apoptosis and potentiates the anti-tumour activity of chemotherapy in rituximab-resistant lymphoma.
The novel proteasome inhibitor carfilzomib induces cell cycle arrest, apoptosis and potentiates the anti-tumour activity of chemotherapy in rituximab-resistant lymphoma.
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DOI：
10.1111/bjh.12452
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发表时间：
2013-09
影响因子：
6.5
通讯作者：
Czuczman MS
中科院分区：
文献类型：
--
作者：
Gu JJ;Hernandez-Ilizaliturri FJ;Kaufman GP;Czuczman NM;Mavis C;Skitzki JJ;Czuczman MS
硼替佐米（BTZ）靶向蛋白酶体系统具有抗肿瘤活性，并增强了化疗/生物制剂在多发性骨髓瘤和b细胞淋巴瘤中的作用。Carfilzomib （CFZ）是一种选择性更强的蛋白酶体抑制剂，在结构上与BTZ不同。为了表征其生物活性，我们在几种淋巴瘤临床前模型中评估了CFZ。利妥昔单抗敏感细胞系（RSCL）、利妥昔单抗耐药细胞系（RRCL）和源自b细胞淋巴瘤患者的原发肿瘤细胞暴露于CFZ或BTZ。测定细胞活力和细胞周期变化。Western blots检测Bcl-2 （BCL2）家族成员中parp的切割和/或变化。CFZ的活性是BTZ的10倍，具有剂量依赖性和时间依赖性的细胞毒性。CFZ暴露通过上调RSCL和RRCL中的Bak （BAK1）和随后的PARP切割诱导细胞凋亡；它也部分依赖于半胱天冬酶。CFZ诱导RSCL细胞G2/M期周期阻滞。CFZ证明了克服RRCL化疗耐药的能力，并增强了化疗药物的抗肿瘤活性。我们的数据表明，CFZ能够克服化疗药物的耐药，上调促凋亡蛋白，促进细胞凋亡，诱导淋巴瘤细胞G2/M细胞周期阻滞。我们的临床前数据支持CFZ在b细胞淋巴瘤中的未来临床评估。
Targeting the proteasome system with bortezomib (BTZ) results in anti-tumour activity and potentiates the effects of chemotherapy/biological agents in multiple myeloma and B-cell lymphoma. Carfilzomib (CFZ) is a more selective proteasome inhibitor that is structurally distinct from BTZ. In an attempt to characterize its biological activity, we evaluated CFZ in several lymphoma pre-clinical models. Rituximab-sensitive cell lines (RSCL), rituximab-resistant cell lines (RRCL), and primary tumour cells derived from B-cell lymphoma patients were exposed to CFZ or BTZ. Cell viability and changes in cell cycle were determined. Western blots were performed to detect PARP-cleavage and/or changes in Bcl-2 (BCL2) family members. CFZ was 10 times more active than BTZ and exhibited dose- and time-dependent cytotoxicity. CFZ exposure induced apoptosis by upregulation of Bak (BAK1) and subsequent PARP cleavage in RSCL and RRCL; it was also partially caspase-dependent. CFZ induced G2/M phase cell cycle arrest in RSCL. CFZ demonstrated the ability to overcome resistance to chemotherapy in RRCL and potentiated the anti-tumour activity of chemotherapy agents. Our data suggest that CFZ is able to overcome resistance to chemotherapeutic agents, upregulate pro-apoptotic proteins to promote apoptosis, and induce G2/M cell cycle arrest in lymphoma cells. Our pre-clinical data supports future clinical evaluation of CFZ in B-cell lymphoma.
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影响因子：
4.6
作者：
Denlinger, CE;Rundall, BK;Jones, DR
通讯作者：
Jones, DR
影响因子：
20.3
作者：
Bil, Jacek;Winiarska, Magdalena;Golab, Jakub
通讯作者：
Golab, Jakub
影响因子：
20.3
作者：
Olejniczak, Scott H.;Blickwedehl, Jennifer;Czuczman, Myron S.
通讯作者：
Czuczman, Myron S.
影响因子：
--
作者：
Jain S;Diefenbach C;Zain J;O'Connor OA
通讯作者：
O'Connor OA
影响因子：
5.7
作者：
Canfield, Steven E.;Zhu, Keyi;McConkey, David J.
通讯作者：
McConkey, David J.