Gut-derived metabolite 3-methylxanthine enhances cisplatin-induced apoptosis via dopamine receptor D1 in a mouse model of ovarian cancer

Abstract

Abstract Background Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms by which the gut microbiota regulates the response to platinum-based therapy remain unclear. Methods To investigate the influence of gut microbiota on the anticancer response, we conducted a study to examine whether antibiotic-induced disruption of gut microbiota affected the efficacy of cisplatin. 16S rRNA sequencing and metabolomic analysis were performed to analyze the alteration in the gut microbiota and fecal metabolism. OC-bearing mice and OC cell lines were used to examine the effect of 3-methylxanthine. Results Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and protein-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. 3-methylxanthine, that significantly enhances the effectiveness of cisplatin by promoting apoptosis both in vivo and in vitro. Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. Conclusions This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediateds cisplaitn induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as an adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.