Lusutrombopag

Platelet (PLT) transfusion was the most practical way to increase patients' PLT counts before invasive hepatic procedures such as radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). A novel drug that raises the PLT count by acting on the thrombopoietin receptor has recently become available.

Lusutrombopag 3 mg was administered daily for 7 days to patients who underwent RFA for liver tumors with low PLT counts (< 50,000 PLT µL^- 1). We collected demographic data concerning the patients' liver function and PLT counts.

Lusutrombopag was administered to 91 patients, with a median age of 71 years (range 51-86). Forty-two patients had hepatitis C, 12 had hepatitis B, 21 had alcoholic liver disease, 11 had nonalcoholic steatohepatitis, and five had other diseases. The median Child-Pugh score was 7 (range 5-11). Thirty-seven patients had stage I tumors, 41 had Stage II, 12 had stage III, and one had stage IV. PLT count was elevated from 4.4 × 10⁴ ± 1.4 × 10⁴ to 8.6 × 10⁴ ± 2.5 × 10⁴ PLT µL^- 1. Lusutrombopag administration prevented PLT transfusions in 84/91 patients (92%). No patient had bleeding complications after RFA. One had portal thrombosis after lusutrombopag administration. Patients who achieved PLT counts of > 50,000 PLT µL^- 1 had higher PLT counts before lusutrombopag administration. The degree of splenomegaly did not affect the rate of PLT count elevation. There was no specific adverse effect by administrating lusutrombopag for patients with PLT counts of around 50,000 µL^- 1 but > 50,000 µL^- 1.

Lusutrombopag administration before RFA was effective and seemed to be relatively safe for hepatocellular carcinoma patients with low PLT counts.

This study was approved by Japanese Red Cross Medical Center Institutional Reseach Comittie (#862, 07/03/2016), and was registered in a publically accessible primary register (#UMIN000046629, registered date: 14/01/2022).

Selenoprotein glutathione peroxidases (GPX), like ubiquitously expressed GPX1 and the ferroptosis modulator GPX4, enact antioxidant activities by reducing hydroperoxides using glutathione. Overexpression of these enzymes is common in cancer and can be associated with the development of resistance to chemotherapy. GPX1 and GPX4 inhibitors have thus shown promise as anti-cancer agents, and targeting other GPX isoforms may prove equally beneficial. Existing inhibitors are often promiscuous, or modulate GPXs only indirectly, so novel direct inhibitors identified through screening against GPX1 and GPX4 could be valuable. Here, we developed optimized glutathione reductase (GR)-coupled GPX assays for the biochemical high-throughput screen (HTS) of almost 12,000 compounds with proposed mechanisms of action. Initial hits were triaged using a GR counter-screen, assessed for isoform specificity against an additional GPX isoform, GPX2, and were assessed for general selenocysteine-targeting activity using a thioredoxin reductase (TXNRD1) assay. Importantly, 70% of the GPX1 inhibitors identified in the primary screen, including several cephalosporin antibiotics, were found to also inhibit TXNRD1, while auranofin, previously known as a TXNRD1 inhibitor, also inhibited GPX1 (but not GPX4). Additionally, every GPX1 inhibitor identified (including omapatrilat, tenatoprazole, cefoxitin and ceftibuten) showed similar inhibitory activity against GPX2. Some compounds inhibiting GPX4 but not GPX1 or GPX2, also inhibited TXNRD1 (26%). Compounds only inhibiting GPX4 included pranlukast sodium hydrate, lusutrombopag, brilanestrant, simeprevir, grazoprevir (MK-5172), paritaprevir, navitoclax, venetoclax and VU0661013. Two compounds (metamizole sodium and isoniazid sodium methanesulfate) inhibited all three GPXs but not TXNRD1, while 2,3-dimercaptopropanesulfonate, PI4KIII beta inhibitor 3, SCE-2174 and cefotetan sodium inhibited all tested selenoproteins (but not GR). The detected overlaps in chemical space suggest that the counter screens introduced here should be imperative for identification of specific GPX inhibitors. With this approach, we could indeed identify novel GPX1/GPX2- or GPX4-specific inhibitors, thus presenting a validated pipeline for future identification of specific selenoprotein-targeting agents. Our study also identified GPX1/GPX2, GPX4 and/or TXNRD1 as targets for several previously developed pharmacologically active compounds.