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Exploring The Impact of Two Novel DNA Minor Groove Binders on HCT-116 Cells: A Comprehensive Multi-Omics Analysis Using Mass Spectrometry

ABSTRACT: Colorectal cancer (CRC) poses a significant global health challenge, necessitating innovative therapeutic approaches. Despite advancements, current treatments encounter obstacles such as chemotherapy resistance and adverse effects due to non-selective targeting. DNA Minor Groove Binders (MGBs) present promising alternatives, targeting DNA structure without causing permanent damage. In this study, two novel MGB compounds were synthesized, MGB30 and MGB32, resembling distamycin, a natural DNA-binding agent. These compounds bind reversibly to the DNA minor groove, influencing DNA structure and inhibiting cancer growth-related enzymes. We conducted mutli-omics approach including metabolomics and proteomics on HCT-116 treated cells to explore the molecular mechanisms of action of MGB30 and MGB32 novel compounds using TIMS-QTOF-UHPLC-MS. We utilized four biological replicates for each treatment condition. By conducting a two-tailed independent student's t-test with q-value < 0.05, 12 metabolites and 187 dysregulated proteins were obtained after MGB30 treatment. Wile 41 metabolites and 409 dysregulated proteins were obtained after MGB32 treatment.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Colon Cancer

SUBMITTER: Core Facility

LAB HEAD: Prof. Mohammad Semreen

PROVIDER: PXD051250 | Pride | 2026-02-04

REPOSITORIES: Pride

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Project description:Prostate cancer poses a significant health risk, ranking as the second most common cancer among men in the United States. However, the effectiveness of current anti-prostate cancer drugs is limited due to increasing drug resistance and side effects. Consequently, there is a pressing need to develop new compounds and identify novel drug targets that can surpass these limitations. Due to their targeted mechanism, DNA minor groove binders (MGBs) are becoming more popular as a relatively safe and effective alternative. In our research, we employed multi-omics techniques to investigate the mechanism of action of a novel MGB compound (MGB4) through LC-MS/MS-based untargeted metabolomics combined with discovery proteomics analysis performed on LNCaP cells, which were treated with MGB4, doxorubicin, or a combination of both compounds. Through a one-way ANOVA test with a significance level of p-value < 0.05, we identified 99 metabolites and 1143 proteins associated with the treatments. Our findings indicate that treating LNCaP cells with doxorubicin or the MGB4 lead compound yielded similar effects, albeit not identical, on the cells. Both compounds deactivated the translation pathway in the cells. Furthermore, we observed alterations in sphingolipid and amino acid metabolic pathways, potentially contributing to the suppression of prostate cancer cell proliferation and division. Additionally, doxorubicin and combined treatments resulted in reduced metabolism of spermine and spermidine, likely stemming from decreased protein synthesis of key enzymes involved in their pathways. Moreover, the combined treatment exhibited a synergistic interaction between the two compounds, leading to altered purine metabolism and a more pronounced reduction in metabolite abundance compared to individual treatments. Overall, our study demonstrates the robustness of the multi-omics approach in elucidating the mechanism of action of promising drug candidates. It also suggests that MGB4 shows potential as a candidate for prostate cancer treatment.

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Exploring The Impact of Two Novel DNA Minor Groove Binders on HCT-116 Cells: A Comprehensive Multi-Omics Analysis Using Mass Spectrometry

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