University of Arizona Cancer Center, College of Medicine, Section of Hematology/Oncology, 1515 N Campbell Ave, Tucson, AZ, USA.
J Exp Clin Cancer Res. 2014 Dec 31;33(1):111. doi: 10.1186/s13046-014-0111-8.
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.
卡非佐米（CFZ）是一种蛋白酶体抑制剂，可选择性且不可逆地与靶标结合，并已在美国获准用于治疗复发性和难治性多发性骨髓瘤。CFZ 的 1B 期研究报告了其在实体瘤中的临床活性信号，包括小细胞肺癌（SCLC）。本研究旨在研究 CFZ 在肺癌模型中的活性。
使用多种人肺癌细胞系和 SHP77 小细胞肺癌异种移植模型来研究 CFZ 的抗肿瘤活性。
CFZ 治疗抑制了肺癌细胞系中的组成型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，96 小时暴露后的 IC50 值为<1.0 nM 至 36 nM。CFZ 在 SHP77 和 DMS114 SCLC 细胞系中的作用更为多变，96 小时时的 IC50 值为<1 nM 至 203 nM。CFZ 处理的 H1993 和 SHP77 细胞的 Western blot 分析显示多聚 ADP 核糖聚合酶（PARP）和 caspase-3 的裂解，表明细胞凋亡，以及微管相关蛋白 1 轻链 3B（LC3B）的诱导，表明自噬。在 SHP77 侧翼异种移植肿瘤中，CFZ 单药治疗抑制肿瘤生长并延长存活时间，而 CFZ +顺铂（CDDP）无相加或协同抗肿瘤疗效。
CFZ 在体外显示出对肺癌细胞系的增殖活性，并在 SHP77 SCLC 异种移植小鼠中导致显著的生存优势，支持 CFZ 在 NSCLC 和 SCLC 中的进一步临床前和临床研究。
