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Identification of a novel minor-groove DNA binder that represses mitochondrial gene expression and induces apoptosis in highly aggressive leiomyosarcoma cells

Eleonora Malavasi,Raffaella Picco,Showmeya Mallavarapu,Martina Minisini,Francesca D'Este,Alessio Bertozzo,Lidia Giuliani,Roberta Astolfi,M. Chinellato,Giacomo Bettin,M. Bortoluzzi,R. Ragno,Alessandro Angelini,Claudio Brancolini

Published 2025 in Cell Death Discovery

ABSTRACT

Leiomyosarcoma (LMS) is an aggressive tumor for which there are few effective therapeutic options. Through a combination of in silico and in vitro screens, we have identified the compound NSC-260594/XMH95 as a promising molecule that selectively induces apoptosis in aggressive LMS cells by upregulating the BH3-only genes PMAP1/NOXA, BIK, HRK and BBC3/PUMA. Similar to the dye Hoechst 33258, XMH95 appears to bind the minor groove of DNA. Unlike Hoechst 33258, XMH95 converts to a fluorescent form only after DNA binding. Furthermore, unlike Hoechst 33258, XMH95 suppresses mitochondrial gene expression and is a more effective inducer of apoptosis. Apart from suppressing mitochondrial genes, XMH95 has many effects on gene expression that it shares with Hoechst 33258. By inhibiting mitochondrial transcription, we show that XMH95 induces apoptosis by impairing both nuclear and mitochondrial transcription. In summary, XMH95 is a novel DNA binder that triggers apoptosis by upregulating multiple BH3-only genes.

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