Carmofur

Abstract: Acute lung injury (ALI), characterized by a severe inflammatory process, is a complex syndrome that can lead to multisystem organ failure. Fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA) are two potential therapeutic targets for inflammation-related diseases. Herein, we identified carmofur, a 5-fluorouracil-releasing drug and clinically used as a chemotherapeutic agent, as a dual FAAH and NAAA inhibitor. In Raw264.7 macrophages, carmofur effectively reduced the mRNA expression of pro-inflammatory factors, including IL-1β, IL-6, iNOS, and TNF-α, and down-regulated signaling proteins of the nuclear transcription factor κB (NF-κB) pathway. Furthermore, carmofur significantly ameliorated the inflammatory responses and promoted resolution of pulmonary injury in lipopolysaccharide (LPS)-induced ALI mice. The pharmacological effects of carmofur were partially blocked by peroxisome proliferator-activated receptor-α (PPARα) antagonist MK886 and cannabinoid receptor 2 (CB2) antagonist SR144528, indicating that carmofur attenuated LPS-induced ALI in a PPARα- and CB2-dependent mechanism. Our study suggested that carmofur might be a novel therapeutic agent for ALI, and drug repurposing may provide us effective therapeutic strategies for ALI.

Abstract: BACKGROUND It is important to identify risk factors for liver metastasis in patients with colorectal carcinoma because the liver is the most common site of recurrence. Alcohol consumption reportedly is associated with hematogenous metastasis in certain animal models. Furthermore, some studies have shown that carmofur, a derivative of 5-fluorouracil, is particularly effective as adjuvant chemotherapy for colorectal carcinoma, and may even suppress liver metastasis, although the mechanism by which this occurs remains unknown. In addition, carmofur is known to inhibit alcohol metabolism. To the authors' knowledge, the relation between liver metastasis in colorectal carcinoma and alcohol consumption has not been examined previously. Therefore, the authors studied the relations between liver metastasis in colorectal carcinoma and various clinicopathologic factors including alcohol consumption status. METHODS This study was comprised of 133 colorectal carcinoma patients with invasion beyond the submucosal layer who had undergone surgical resection. The subjects were examined and divided into two groups according to the occurrence or absence of liver metastasis. The relations between liver metastasis and other clinicopathologic factors were analyzed by univariate and multivariate statistical methods. RESULTS Univariate analysis showed alcohol consumption (P = 0.0021) and blood vessel invasion (P = 0.0045) were correlated with liver metastasis. Multivariate analysis showed both to be independent risk factors for liver metastasis. CONCLUSIONS Alcohol consumption is an independent risk factor for liver metastasis in colorectal carcinoma patients. Therefore, patients with colorectal carcinoma who drink alcohol require intensive examination and follow-up with respect to liver metastasis. Further study is necessary to confirm the effect of adjuvant chemotherapy using carmofur in colorectal carcinoma patients. Cancer 1998;83:1483-1488. © 1998 American Cancer Society.

Abstract: The antineoplastic drug Carmofur was shown to inhibit SARS-CoV-2 main protease (Mpro). Here the X-ray crystal structure of Mpro in complex with Carmofur reveals that the carbonyl reactive group of Carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC50 = 24.30 μM) and it is a promising lead compound to develop new antiviral treatment for COVID-19.