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Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

ABSTRACT: Multiple myeloma RPMI8226 cells adapted to growth in melphalan display a shift towards Warburg metabolism and modulated oxidative stress signaling Inhibitors targeting specific enzymes in these pathways are selectively toxic to the melphalan-resistant cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60970 | GEO | 2014/09/03

SECONDARY ACCESSION(S): PRJNA260009

REPOSITORIES: GEO

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Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

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Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

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Metabolic Changes Contribute to Melphalan Resistance in Multiple Myeloma

Project description:Multiple myeloma is an incurable hematological malignancy that impacts tens of thousands of people every year in the U.S. Treatment for eligible patients includes three stages: induction, consolidation with stem cell rescue, and maintenance. High dose therapy with the DNA alkylating agent, melphalan, remains the primary drug for consolidation therapy in conjunction with autologous stem cell transplant. As a result, melphalan resistance remains a clinical challenge. Here, we use proteometabolomics to examine mechanisms of melphalan resistance in two cell line models. Drug metabolism, steady-state metabolomics, activity-based protein profiling (ABPP), acute treatment metabolomics, and immunoblotting analyses have allowed us to further elucidate metabolic processes contributing to melphalan resistance. Proteometabolomics data indicate that both drug resistant cells have higher levels of pentose phosphate pathway metabolites than their naïve counterparts. Interestingly, we also observed cell line specific changes in purine, pyrimidine and glutathione metabolism that are linked to the differences in steady state metabolism of naïve cells and highlight the heterogeneity of melphalan resistance in these models. Because of the diversity of metabolic changes, our data suggest that omics approaches will be needed to fully examine melphalan resistance in patient specimens and define personalized strategies to optimize the delivery of this therapy.

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Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells.

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