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An Integrated Workflow of Identification and Quantification on FDR Control-Based Untargeted Metabolome
Published on: September 20, 2022
Preclinical studies on metal based anticancer drugs as enabled by integrated metallomics and metabolomics
Luis Galvez1, Mate Rusz, Michaela Schwaiger-Haber
1Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 38, 1090 Vienna, Austria. gunda.koellensperger@univie.ac.at.
Abstract:
Resistance development is a major obstacle for platinum-based chemotherapy, with the anticancer drug oxaliplatin being no exception. Acquired resistance is often associated with altered drug accumulation. In this work we introduce a novel -omics workflow enabling the parallel study of platinum drug uptake and its distribution between nucleus/protein and small molecule fraction along with metabolic changes after different treatment time points. This integrated metallomics/metabolomics approach is facilitated by a tailored sample preparation workflow suitable for preclinical studies on adherent cancer cell models. Inductively coupled plasma mass spectrometry monitors the platinum drug, while the metabolomics tool-set is provided by hydrophilic interaction liquid chromatography combined with high-resolution Orbitrap mass spectrometry. The implemented method covers biochemical key pathways of cancer cell metabolism as shown by a panel of >130 metabolite standards. Furthermore, the addition of yeast-based 13C-enriched internal standards upon extraction enabled a novel targeted/untargeted analysis strategy. In this study we used our method to compare an oxaliplatin sensitive human colon cancer cell line (HCT116) and its corresponding resistant model. In the acquired oxaliplatin resistant cells distinct differences in oxaliplatin accumulation correlated with differences in metabolomic rearrangements. Using this multi-omics approach for platinum-treated samples facilitates the generation of novel hypotheses regarding the susceptibility and resistance towards oxaliplatin.
Insights
Developing resistance to oxaliplatin chemotherapy is a challenge. This study introduces a novel multi-omics workflow to analyze platinum drug uptake and metabolic changes in cancer cells, revealing key differences in resistant models.
Area of Science:
- Biochemistry
- Pharmacology
- Cancer Research
Background:
- Platinum-based chemotherapy, including oxaliplatin, faces significant challenges due to acquired drug resistance in cancer cells.
- Altered drug accumulation is a common mechanism underlying this acquired resistance.
- Understanding the interplay between drug distribution and cellular metabolism is crucial for overcoming resistance.
Purpose of the Study:
- To introduce and validate a novel multi-omics workflow for parallel analysis of platinum drug uptake and metabolic alterations in cancer cells.
- To investigate the differences in oxaliplatin accumulation and metabolic profiles between sensitive and resistant cancer cell lines.
- To generate new hypotheses regarding oxaliplatin susceptibility and resistance mechanisms.
Main Methods:
- Development of an integrated metallomics and metabolomics workflow using inductively coupled plasma mass spectrometry (ICP-MS) for platinum detection and hydrophilic interaction liquid chromatography-Orbitrap mass spectrometry (HILIC-Orbitrap-MS) for metabolite profiling.
- Tailored sample preparation optimized for preclinical studies with adherent cancer cell models.
- Utilized yeast-based 13C-enriched internal standards for a combined targeted and untargeted metabolomics analysis covering over 130 metabolite standards and key cancer cell metabolic pathways.
Main Results:
- The study successfully applied the developed multi-omics workflow to compare an oxaliplatin-sensitive human colon cancer cell line (HCT116) with its resistant counterpart.
- Distinct differences in oxaliplatin accumulation were observed in the resistant cells.
- These differences in drug accumulation significantly correlated with notable rearrangements in the metabolomic profiles of the resistant cells.
Conclusions:
- The novel integrated metallomics/metabolomics approach provides a powerful tool for studying platinum-based drug resistance in cancer.
- The findings highlight a correlation between oxaliplatin accumulation and metabolic reprogramming in resistant cancer cells.
- This multi-omics strategy facilitates the generation of novel, testable hypotheses concerning oxaliplatin efficacy and resistance mechanisms.
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