O6-methylguanine-DNA methyltransferase inhibition leads to cellular senescence and vascular smooth muscle dysfunction
Year: 2025
Type: article
Abstract: Inhibiting O6-methylguanine-DNA methyltransferase (MGMT) is crucial for overcoming chemoresistance to alkylating agents, though its use is limited by myelosuppression. Beyond bone marrow, other adverse effects were not studied. Given chemotherapy-induced senescence in healthy tissues, e.g., cardiovascular damage, we investigated the impact of the MGMT inhibitor O6-benzylguanine (BG) on aortic vascular smooth muscle cells (VSMCs) and aorta. Starting on day 3 of BG incubation, VSMCs exhibited altered morphology, reduced growth, increased SAβGal activity and elevated senescence markers p27 or γH2A.X. BG activated senescence-related pathways, including Erk1/2, p38α, Akt and mTORC1; induced BCl2, MnSOD and CDK1; and decreased αSMA and skp2 levels. These changes suggest BG-induced γH2A.X, p38 and Akt activation, resulting in G2/M cell cycle arrest via pCDK1. Functionally, BG impaired the vascular reactivity of aortic rings to phenylephrine, isoprenaline and sodium nitrite. In rats, systemic BG administration similarly reduced the response to sodium nitrite but left phenylephrine and isoprenaline responses unchanged. Our findings highlight BG’s potential adverse effects on vascular smooth muscle, marked by senescence activation and reduced vascular reactivity. These results emphasise the need for caution in the clinical use of MGMT inhibitors. Furthermore, we present the model of senescence in primary VSMCs characterised by the expression of several senescence markers and G2/M checkpoint arrest. • O6-benzylguanine induces senescence in aortic vascular smooth muscle cells. • Senescence markers p27 and γH2A.X were elevated in treated cells. • Erk1/2, p38, Akt, and mTORC1 pathways showed increased activation. • Vascular reactivity to PE, ISO, and SN was significantly reduced. • Future studies on MGMT inhibitors should assess cardiovascular effects.
Source: Biomedicine & Pharmacotherapy
Institution: Comenius University Bratislava
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,610
OpenAlex ID: W4409869566