Alleviation of the drug-resistant phenotype in idarubicin and cytosine arabinoside double-resistant acute myeloid leukemia cells by indomethacin

Abstract

Chemoresistance to anticancer drugs is a major issue in the successful treatment of acute myeloid leukemia (AML). In this study, we developed an AML cell line (AML-2/IDAC) that is resistant to treatment with a combination of idarubicin and cytosine arabinoside (Id/AraC) by chronic exposure for more than 3 months. We then investigated the ability of indomethacin to alleviate the chemoresistance of AML-2/IDAC cells. Treatment with indomethacin alone induced growth arrest, but not the death of AML-2/IDAC cells. However, when AML-2/IDAC cells were treated with combinations of indomethacin and Id/AraC, the cell death and apoptosis rate of AML-2/IDAC cells were significantly increased in a dose-and time-dependent manner. The combined treatment with indomethacin and Id/AraC caused the collapse of the mitochondrial membrane potential and was also demonstrated to enhance the activities of caspase-3 and-8 in AML-2/IDAC cells. Furthermore, indomethacin down-regulated expression of the ABCA3 and MRP1 genes, which were over-expressed in AML-2/IDAC cells. Taken together, the results of this study suggest that indomethacin can be used to increase the therapeutic potential against drug-resistant AML when combined with anti-leukemic drugs.

Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3

“…5C). Indometacin had been shown to suppress the expression of ABCA3 in acute myeloid leukemia cells, restoring susceptibility to cytostatic therapy (28). Indeed, indometacin strongly diminished ABCA3 expression in our B-cell lymphoma cell lines (Fig.…”

“…For indometacin, the central mechanism of inhibiting exosome release appears to be the down-regulation of ABCA3 expression at the transcriptional level (Fig. S7A) (28). Anti-cancer effects of indometacin have been consistently observed both clinically and in preclinical model systems (48).…”

Nuclear Trapping through Inhibition of Exosomal Export by Indomethacin Increases Cytostatic Efficacy of Doxorubicin and Pixantrone

“…Thus we extrapolate that the doses of indomethacin sufficient to modulate doxorubicin and pixantrone in the CAM assay setting may reflect clinically achievable concentrations The combination of COX inhibition and chemotherapy has been applied to patients with non-small cell lung cancer with promising results, yet only with schedules containing taxanes and platinum (43). To the best of our knowledge and in contrast with some in vitro evidence presented here and elsewhere (28,29,(44)(45)(46), the clinical outcome of an anthracycline/COX inhibitor combination has not yet been reported, not as a designated clinical trial nor as retrospective series summarizing the inadvertently coincidental use of both classes of drugs. While we share the concerns of combining a conventional anthracycline with indomethacin, we propose, taking into account the low cardiac toxicity of pixantrone, the cotreatment of indomethacin and pixantrone as an effective and feasible regimen to be tested in a clinical trial.…”

“…3A). We and others recently identified the cyclooxygenase inhibitor indomethacin as a drug resistance modulator (16,(27)(28)(29) with suppression of ABCA3 expression on the transcriptional level (16,28,30). Importantly, indomethacin cotreatment almost completely diminished the doxorubicin-induced increase in ABCA3 expression after doxorubicin ( Fig.…”

Activation of peroxisome proliferator-activated receptor-γ induces apoptosis on acute promyelocytic leukemia cells via downregulation of XIAP

“…Many studies show that defects in apoptosis signaling contribute to cancer cell drug resistance, and activation of apoptosis pathways is a key mechanism by which cytotoxic drugs kill cancer cells (13)(14)(15). Thus, induction of apoptosis is now considered as an important method of assessment for the clinical effectiveness of many anti-cancer drugs (16,17).…”