Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.
Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models.
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DOI：
10.1186/s13046-014-0111-8
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发表时间：
2014-12-31
期刊：
影响因子：
--
通讯作者：
Garland LL
中科院分区：
文献类型：
--
作者：
Baker AF;Hanke NT;Sands BJ;Carbajal L;Anderl JL;Garland LL
卡非佐米（CFZ）是一种蛋白酶体抑制剂，可选择性和不可逆地结合其靶点，已在美国获批用于治疗复发性和难治性多发性骨髓瘤。CFZ的1B期研究报告了在实体瘤（包括小细胞肺癌（SCLC））中的临床活性信号。本研究的目的是研究CFZ在肺癌模型中的活性。一组不同的人肺癌细胞系和SHP 77小细胞肺癌异种移植模型用于研究CFZ的抗肿瘤活性。CFZ处理抑制肺癌细胞系中的组成性蛋白酶体和免疫蛋白酶体。CFZ在A549、H1993、H520、H460和H1299非小细胞肺癌（NSCLC）细胞系中具有显著的抗增殖活性，暴露96小时后的IC 50值为<1.0 nM至36 nM。CFZ在SHP 77和DMS 114 SCLC细胞系中具有更可变的作用，96小时的IC 50值从<1 nM至203 nM。CFZ处理的H1993和SHP 77细胞的蛋白质印迹分析显示聚ADP核糖聚合酶（PARP）和半胱天冬酶-3的裂解，指示凋亡，以及微管相关蛋白-1轻链-3B（LC 3B）的诱导，指示自噬。在SHP 77侧腹异种移植肿瘤中，CFZ单药治疗可抑制肿瘤生长并延长生存期，而CFZ +顺铂（CDDP）未观察到累加或协同抗肿瘤疗效。CFZ在体外肺癌细胞系中表现出抗增殖活性，并在SHP 77 SCLC异种移植小鼠中产生显著的生存优势，支持CFZ在NSCLC和SCLC中的进一步临床前和临床研究。本文的在线版本（doi：10.1186/s13046-014-0111-8）包含补充材料，可供授权用户使用。
Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC50 values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC50 values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC. The online version of this article (doi:10.1186/s13046-014-0111-8) contains supplementary material, which is available to authorized users.
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影响因子：
20.4
作者：
Davies, Angela M.;Ruel, Christopher;Gandara, Anddavid R.
通讯作者：
Gandara, Anddavid R.
影响因子：
5.3
作者：
Li, Tianhong;Ho, Liawaty;Gucalp, Rasim
通讯作者：
Gucalp, Rasim
DOI：
10.1186/1756-9966-29-8
发表时间：
2010-01-22
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Ling X;Calinski D;Chanan-Khan AA;Zhou M;Li F
通讯作者：
Li F
DOI：
10.1097/jto.0b013e3181915052
发表时间：
2009-01
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Davies AM;Chansky K;Lara PN Jr;Gumerlock PH;Crowley J;Albain KS;Vogel SJ;Gandara DR;Southwest Oncology Group
通讯作者：
Southwest Oncology Group
影响因子：
6.2
作者：
Ludwig, H;Khayat, D;Facon, T
通讯作者：
Facon, T