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THZ1, a CDK7 inhibitor, has potent antitumor effects in several cancers; however, its role in Acute myeloid leukemia (AML) is unclear. We explored the effects and potential mechanisms of THZ1, alone and in combination with azacitidine (AZA), in AML cells and xenograft models. THZ1 decreased cell viability, induced apoptosis in a dose and time-dependent manner, induced G0/G1 cell cycle arrest, decreased phosphorylated CDK1 and CDK2 expression, and inhibited RNA Pol II phosphorylation at multiple serine sites. The combination of AZA and THZ1 exhibited synergistic antileukemic effects in AML cell lines and primary cells with MCL1 and c-MYC downregulation. Moreover, the combination therapy significantly decreased tumor burden and prolonged animal survival in xenograft mice models. Our data demonstrate that CDK7 inhibition induces the apoptosis of AML cells and exerts a synergistic antileukemia effect with AZA in vitro and in vivo, which supports future exploration of this combination in clinical studies. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD), including heart attack, stroke, heart failure, arrhythmia, and other congenital heart diseases remain the leading cause of morbidity and mortality worldwide. The leading cause of deaths in CVD is attributed to myocardial infarction due to the rupture of atherosclerotic plaque. Atherosclerosis refers a condition when restricted or even blockage of blood flow occurs due to the narrowing of blood vessels as a result of the buildup of plaques composed of oxidized lipids. It is well-established that free radical oxidation of polyunsaturated fatty acids (PUFAs) in lipoproteins or cell membranes, termed lipid peroxidation (LPO), plays a significant role in atherosclerosis. LPO products are involved in immune responses and cell deaths in this process, in which previous evidence supports the role of programmed cell death (apoptosis) and necrosis. Ferroptosis is a newly identified form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels, which exhibits distinct features from apoptosis, necrosis and autophagy in morphology, biochemistry and genetics. Emerging evidence appears to demonstrate that ferroptosis is also involved in CVD. In this review, we summarize the recent progress on ferroptosis in CVD and atherosclerosis, highlighting the role of free radical LPO. The evidence underlying the ferroptosis and challenges in the field will also be critically discussed. [ABSTRACT FROM AUTHOR]