Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer

Abstract

Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies. Currently, there is no standard or effective therapy for ATC. Drug repurposing for cancer treatment is an emerging approach for identifying compounds that may have antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines. Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three proteasome inhibitors screened, a second-generation proteasome inhibitor, carfilzomib, was the most active. Treatment of ATC cells with carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically, carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the anti-apoptotic protein ATF4. Pretreatment with carfilzomib reduced in vivo metastases (lung, bone, liver, and kidney) and disease progression, and decreased N-cadherin expression. Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.

Second-generation proteasome inhibitor carfilzomib enhances doxorubicin-induced cytotoxicity and apoptosis in breast cancer cells

“…IC50 values for the tested cell lines treated with CFZ were all in the low nanomolar range from 6.34 nM (MDA-MB-361) to 76.51 nM (T-47D), there was more than 10-fold difference. This is similar to the reported CFZ IC50 values (0.2 nM −99.4 nM) in other solid tumor cell lines [11, 12], and it implies that the different subtypes of breast cancer cell lines might show the sensitivity difference to CFZ. It's worth mentioning that the anchorage-independent growth ability of HCC1954 was too poor to form macroscopic colonies in soft agar.…”

“…These data suggest that CFZ alone could effectively restrain proteasome activity and has a significant antitumor effect on the tested breast cancer cells. Similarly, studies with CFZ have demonstrated that CFZ causes diminished cell proliferation and increased cell death across a variety of cancer cell lines such as those from lung cancer and anaplastic thyroid cancer [11, 12, 29]. …”

“…CFZ overcomes bortezomib resistance and lessens side effects in patients treated with bortezomib [9]. These agents have also been studied in solid tumors in a number of phase I and II clinical trials [11, 12], yet they have not shown consistent antitumor activity in solid tumors. At present, the effect of carfilzomib on breast cancer cell proliferation remains unclear.…”

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.…”

Second-generation proteasome inhibitor carfilzomib sensitizes neuroblastoma cells to doxorubicin-induced apoptosis

“…Therefore, the proteasome inhibitor presents itself as a promising anticancer agent. According to prior studies, proteasome inhibitors, such as Bortezomib, Ixazomib [44, 45], and Carfilzomib [26] [46, 47] have demonstrated therapeutic efficacy in a variety of cancer types. CFZ, which is approved by the FDA for treating the relapsed and refractory multiple myeloma, proved to be tolerable with high efficacy and safety in solid tumors, including lung cancer, head and neck squamous cell carcinoma, and glioblastoma [46] [48, 49].…”