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Abstract
BackgroundAcute myeloid leukemia (AML) is a hematological malignancy with a dismal prognosis. For over four decades, AML has primarily been treated by cytarabine combined with an anthracycline. Although a significant proportion of patients achieve remission with this regimen, roughly 40% of children and 70% of adults relapse. Over 90% of patients with resistant or relapsed AML die within 3 years. Thus, relapsed and resistant disease following treatment with standard therapy are the most common clinical failures that occur in treating this disease. In this study, we evaluated the relationship between AML cell line global metabolomes and variation in chemosensitivity.MethodsWe performed global metabolomics on seven AML cell lines with varying chemosensitivity to cytarabine and the anthracycline doxorubicin (MV4.11, KG-1, HL-60, Kasumi-1, AML-193, ME1, THP-1) using ultra-high performance liquid chromatography – mass spectrometry (UHPLC-MS). Univariate and multivariate analyses were performed on the metabolite peak intensity values from UHPLC-MS using MetaboAnalyst to identify cellular metabolites associated with drug chemosensitivity.ResultsA total of 1,624 metabolic features were detected across the leukemic cell lines. Of these, 187 were annotated to known metabolites. With respect to doxorubicin, we observed significantly greater abundance of a carboxylic acid (1-aminocyclopropane-1-carboxylate) and several amino acids in resistant cell lines. Pathway analysis found enrichment of several amino acid biosynthesis and metabolic pathways. For cytarabine resistance, nine annotated metabolites were significantly different in resistance vs. sensitive cell lines, including D-raffinose, guanosine, inosine, guanine, aldopentose, two xenobiotics (allopurinol and 4-hydroxy-L-phenylglycine) and glucosamine/mannosamine. Pathway analysis associated these metabolites with the purine metabolic pathway.ConclusionOverall, our results demonstrate that metabolomics differences contribute toward drug resistance. In addition, it could potentially identify predictive biomarkers for chemosensitivity to various anti-leukemic drugs. Our results provide opportunity to further explore these metabolites in patient samples for association with clinical response.
Highlights
Acute myeloid leukemia (AML) is a hematological disease resulting from proliferation and expansion of malignant myeloid cells
Cell lines were categorized as sensitive or resistant to treatment based on area under the survival cure (AUC) values for cytarabine and doxorubicin obtained from in vitro cytotoxicity determined using MTT assays
We evaluated the global metabolic profiles of seven AML cell lines with varying sensitivity to two of the most commonly used chemotherapeutic agents used for treatment of AML: cytarabine and doxorubicin
Summary
Acute myeloid leukemia (AML) is a hematological disease resulting from proliferation and expansion of malignant myeloid cells. Despite being so well established, the rates of achieving complete remission with the 7 + 3 regimen are approximately 70% in patients 60 years old [2,3,4]. One of the major causes of these poor treatment outcomes is the development of resistance to the chemotherapeutic agents used in standard treatment regimens. Cancer cells that are able to adapt and resist induction therapy are frequently the cause of relapse, and often lead to a worse prognosis for patients. A significant proportion of patients achieve remission with this regimen, roughly 40% of children and 70% of adults relapse. Relapsed and resistant disease following treatment with standard therapy are the most common clinical failures that occur in treating this disease. We evaluated the relationship between AML cell line global metabolomes and variation in chemosensitivity
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