Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models

Abstract

BackgroundCarfilzomib (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.MethodsA 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.ResultsCFZ 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).ConclusionsCFZ 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-014-0111-8) contains supplementary material, which is available to authorized users.

Polymer Nanoassemblies With solvato- and halo-fluorochromism for Drug Release Monitoring and Metastasis Imaging

“…Carfilzomib (CFZ), a US FDA approved proteasome inhibitor, was used in this study as a model anticancer drug that is clinically relevant, nonfluorescent, practically insoluble (log p = 4.2) and unionizable in physiological conditions (pKa = 3.5). Traditionally, carfilzomib has been used to treat hematological malignancies such as multiple myeloma, but there is growing interest in the use of carfilzomib to treat solid tumors and tumor metastasis [30,31]. The NB-conjugated TNAs were designed to monitor the amount of drug remaining in the hydrophobic core of polymer nanoassemblies in solution in real time, and detect metastatic tumors in a tissue pH-dependent manner.…”

Emerging role of immunoproteasomes in pathophysiology

“…To overcome these ill‐effects, efforts are being made to design selective inhibitors that specifically target immunoproteasome subunits 6 . From this perspective, the potential for the utilization of immunoproteasome inhibitors in the treatment of diseases is worth exploring 8 , 9 . Therefore, this review explores the relationship between the immunoproteasome profiles and various pathological conditions to guide future research.…”

Elevated RABEX-5 protein expression predicts poor prognosis in combined small cell lung cancer

“…Although the response to chemotherapy was poorer in C-SCLC compared to pure SCLC [4], the NCCN guidelines still recommend the etoposide and cisplatin as the first-line therapy of C-SCLC [5][6][7]. Interestingly, a recent study found that C-SCLC may have many of the features of NSCLC [8][9][10]. These results showed that the C-SCLC has its own clinicopathological characteristics.…”