Anti-Ferroptosis Drug Enhances Total-Body Irradiation Mitigation by Drugs that Block Apoptosis and Necroptosis.

Radiation Research
Stephanie ThermozierJoel S Greenberger

Abstract

Mitigation of total-body irradiation (TBI) in C57BL/6 mice by two drugs, which target apoptosis and necroptosis respectively, increases survival compared to one drug alone. Here we investigated whether the biomarker (signature)directed addition of a third anti-ferroptosis drug further mitigated TBI effects. C57BL/6NTac female mice (30-33 g) received 9.25 Gy TBI, and 24 h or later received JP4-039 (20 mg/kg), necrostatin-1 (1.65 mg/kg) and/or lipoxygenase-15 inhibitor (baicalein) (50 mg/kg) in single-, dual- or three-drug regimens. Some animals were sacrificed at days 0, 1, 2, 3, 4 or 7 postirradiation, while the majority in each group were maintained beyond 30 days. For those mice sacrificed at the early time points, femur bone marrow, intestine (ileum), lung and blood plasma were collected and analyzed for radiation-induced and mitigator-modified levels of 33 pro-inflammatory and stress response proteins. Each single mitigator administered [JP4-039 (24 h), necrostatin-1 (48 h) or baicalein (24 h)] improved survival at day 30 after TBI to 25% (P = 0.0432, 0.2816 or 0.1120, respectively) compared to 5% survival of 9.25 Gy TBI controls. Mice were administered the drug individually based on weight (mg/kg). Drug vehicles comprised ...Continue Reading

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Citations

Aug 19, 2020·Antioxidants & Redox Signaling·Behrouz HassanniaTom Vanden Berghe
Apr 25, 2020·International Journal of Molecular Sciences·Qingya ShiIvet Bahar
Jan 20, 2021·International Journal of Radiation Biology·Xiaohong ZhangHaiqian Zhang
May 21, 2021·Biochemical and Biophysical Research Communications·Meng YangYeqiang Song
Aug 21, 2021·Journal of Drug Targeting·Zhe ChenLinxi Chen

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis