Work

SKI-606, a Src inhibitor, ameliorates benzene-induced hematotoxicity via blocking ROS/Src kinase-mediated p38 and Akt signaling pathways

Year: 2024

Type: article

Abstract: Exposure to benzene causes acute myelosuppression and other hematologic disorders. However, the detailed mechanism by which benzene exerts its severe hematotoxicity and potential treatments still require further deciphering and exploration. Herein, we found that hydroquinone (HQ), a main benzene metabolite, significantly increased intracellular reactive oxygen species (ROS) formation and subsequently caused damage to DNA, leading to impaired colony formation capacity and induction of apoptosis in human hematopoietic stem/progenitor cells (HSPCs) in vitro . The effects were mediated by activation of Src kinase, which subsequently activated the p38 signaling pathway while inhibiting the Akt signaling pathway. The mechanism was further verified by pre-treatment with a Src kinase inhibitor SKI-606, which effectively reversed the dampened self-renewal capacity and increased apoptosis of HSPCs induced by HQ in vitro . Furthermore, administration of SKI-606 partially reversed benzene-induced hematotoxicity and prolonged the survival time in benzene-poisoned mice. Taken together, these findings highlight that HQ-induced hematotoxicity in HSPCs is attributed to the Src kinase-mediated activation of p38 signaling pathway and repression of Akt signaling pathway. Notably, SKI-606 as a tyrosine kinase inhibitor may be a promising and potential agent for alleviating benzene-induced hematotoxicity. • Benzene induces hematotoxicity through activating ROS-dependent Src kinase in HSPCs. • Hydroquinone, a main benzene metabolite, upregulates p38 phosphorylation in HSPCs while downregulating Akt phosphorylation. • SKI-606, a Src inhibitor, can ameliorate benzene-induced hematotoxicity in vitro and in vivo .

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2024.117223