Exploring the Impact of Two DNA Minor Groove Binder Compounds on HCT-116 Cells: A Comprehensive Multiomics Analysis...

Area of Science:

• Molecular biology
• Cancer research
• Metabolomics and proteomics

Background:

• Colorectal cancer (CRC) is a significant global health challenge requiring novel therapies.
• DNA minor groove binders (MGBs) are a class of compounds that interact with DNA without causing permanent damage.
• Distamycin-like MGBs offer potential for targeted cancer treatment.

Purpose of the Study:

• To investigate the molecular mechanisms of action of MGB30 and MGB32 in human colorectal cancer cells (HCT-116).
• To elucidate the downstream effects of these MGBs on cellular metabolism and protein synthesis.

Main Methods:

• Utilized an integrated multiomics approach combining metabolomics and proteomics.
• Employed TIMS-QTOF-UHPLC-MS for high-resolution analysis.
• Analyzed four biological replicates per treatment condition.

Main Results:

• MGB30 altered 12 metabolites and 187 proteins; MGB32 altered 41 metabolites and 409 proteins (q-value <0.05).
• Both compounds disrupted purine metabolism; MGB32 also affected beta-alanine metabolism, glutathione metabolism, and spermidine/spermine biosynthesis.
• Proteomics revealed MGBs deactivated RNA processing, translation, and ribosome biogenesis, impairing protein synthesis and reducing cell proliferation.

Conclusions:

• MGB30 and MGB32 exhibit distinct molecular mechanisms in colorectal cancer cells.
• These MGBs disrupt critical metabolic pathways and protein synthesis, leading to reduced cancer cell proliferation.
• The findings provide mechanistic insights for developing novel MGB-based therapies for colorectal cancer.