Untargeted Multiomics of LNCaP Cell Line Treated with a Novel DNA Minor Groove Binder and/or Doxorubicin Using Mass Spectrometry

Prostate cancer (PCa) remains a major global health concern, ranking among the most prevalent cancer in men worldwide. Despite the availability of various therapeutic options, the clinical efficacy of current anti-PCa agents is often compromised by drug resistance and adverse effects. DNA minor groove binders offer a potential therapeutic alternative, owing to their selective mechanism of action and favorable safety profiles. In the present study, we utilized a multiomics strategy to investigate the molecular impact of novel compound MGB4. LNCaP cells were treated with doxorubicin, MGB4, or a combination of both, followed by LC-MS/MS-based untargeted proteomics and metabolomics analyses. One-way ANOVA (<i>p</i>-value <0.05) revealed 55 significantly dysregulated proteins and 57 altered metabolites across treatments. Our findings indicate that both MGB4 and doxorubicin impacted key cellular pathways, including inhibition of translation and alterations in sphingolipid and amino acid metabolism, while doxorubicin and the combination therapy also reduced spermine and spermidine metabolism. Notably, the combined treatment exhibited synergistic effects, significantly impacting purine metabolism and reducing metabolite levels more than individual therapies. This study provides key molecular insights into MGB4 and doxorubicin's mechanisms, supporting MGB4 as a potential prostate cancer drug candidate.