Untargeted Multiomics of LNCaP Cell Line Treated with a Novel DNA Minor Groove Binder and/or Doxorubicin Using Mass
Ruba A Zenati1,2, Nelson C Soares3,4,5,6, Hasan Y Alniss1,2
1Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates.
Abstract:
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 (p-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.
Insights
Novel compound MGB4 shows promise as a prostate cancer (PCa) therapeutic. Multiomics analysis revealed MGB4 and doxorubicin impact translation and metabolism, with combination therapy showing synergistic effects.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer (PCa) is a leading global health issue for men.
- Current therapies face challenges due to drug resistance and side effects.
- DNA minor groove binders present a promising therapeutic avenue with selective action.
Purpose of the Study:
- To investigate the molecular mechanisms of novel compound MGB4 in prostate cancer.
- To compare the effects of MGB4, doxorubicin, and their combination using a multiomics approach.
- To evaluate MGB4 as a potential drug candidate for prostate cancer treatment.
Main Methods:
- Utilized a multiomics strategy involving LC-MS/MS-based untargeted proteomics and metabolomics.
- Treated LNCaP cells with doxorubicin, MGB4, or a combination of both.
- Analyzed significantly dysregulated proteins and metabolites using one-way ANOVA (p<0.05).
Main Results:
- Identified 55 significantly dysregulated proteins and 57 altered metabolites.
- Both MGB4 and doxorubicin affected translation, sphingolipid, and amino acid metabolism.
- Combination therapy demonstrated synergistic effects, impacting purine metabolism and polyamine metabolism more significantly.
Conclusions:
- MGB4 impacts key cellular pathways relevant to prostate cancer.
- Combined treatment with doxorubicin shows enhanced efficacy and synergistic effects.
- MGB4 is a potential candidate for novel prostate cancer therapy.
