Abstract
Previously, arsenic trioxide showed impressive regression rates of acute promyelocytic leukemia. Here, we investigated molecular determinants of sensitivity and resistance of cell lines of different tumor types towards arsenic trioxide. Arsenic trioxide was the most cytotoxic compound among 8 arsenicals investigated in the NCI cell line panel. We correlated transcriptome-wide microarray-based mRNA expression to the IC50 values for arsenic trioxide by bioinformatic approaches (COMPARE and hierarchical cluster analyses, Ingenuity signaling pathway analysis). Among the identified pathways were signaling routes for p53, integrin-linked kinase, and actin cytoskeleton. Genes from these pathways significantly predicted cellular response to arsenic trioxide. Then, we analyzed whether classical drug resistance factors may also play a role for arsenic trioxide. Cell lines transfected with cDNAs for catalase, thioredoxin, or the anti-apoptotic bcl-2 gene were more resistant to arsenic trioxide than mock vector transfected cells. Multidrug-resistant cells overexpressing the MDR1, MRP1 or BCRP genes were not cross-resistant to arsenic trioxide. Our approach revealed that response of tumor cells towards arsenic trioxide is multi-factorial.
Highlights
Arsenic is a natural semimetal in soil, water and air
The inactive or weakly active arsenicals were arsenic(III) 2,3-dimercapto succinic acid, simethyl arsinic acid, lithiume arsenate (Li3AsO4), sodium arsenic tungsten polyoxymetalate hydrate, and arsenic acid (H3AsO4) trilithium salt. These substances have been investigated over a dose range from 1028 to 1024 M in 60 tumor cell lines and inhibition concentration 50% (IC50) values have been calculated thereof
As multidrug resistance (MDR) and MDR-conferring drug transporters of the ATP-binding cassette (ABC) transporter family are a major cause of failure to many established anti-cancer drugs, we addressed the question, whether cellular response to arsenic trioxide treatment may be affected by ABC transporters
Summary
Arsenic is a natural semimetal in soil, water and air. It exists as red arsenic (As2S2), yellow arsenic (As2S3), white arsenic (As2O3, arsenic trioxide), phenylarsine oxide (C6H5AsO), and as salts of sodium, potassium and calcium [1]. The revival of arsenic in modern medicine was initiated by Chinese scientists showing dramatic regression rates of acute promyelocytic leukemia by arsenic trioxide [6]. These findings were subsequently corroborated in clinical studies in the USA [7]
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