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Nucleoside analog ARC targets Mcl-1 to induce apoptosis in leukemia cells

Leukemia volume 24, pages 851–855 (2010)Cite this article

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Earlier, we identified a nucleoside analog named ARC (4-amino-6-hydrazino-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide), which is a CDK9/transcriptional inhibitor.1 We and others showed that ARC selectively induced potent apoptosis in neuroblastoma,2 melanoma3 and other cancer cells,4, 5 whereas it did not induce apoptosis in normal cells. In addition, ARC showed strong antiangiogenic activity in vitro.1 ARC-induced apoptosis correlated with suppression of labile antiapoptotic protein Mcl-1,2, 3, 4 and Mcl-1 overexpression protected melanoma and neuroblastoma cells from ARC-induced apoptosis.2, 3 Abbott laboratories (Abbott Park, IL, USA) introduced Bcl-2/Bcl-XL inhibitor ABT-737 that competes with BAD for docking to the hydrophobic groove of Bcl-2 and augments Bax and Bak activation.6 ABT-737 does not inhibit Mcl-1, and cancer cells with high levels of Mcl-1 are resistant to ABT-737.6 Downregulation of Mcl-1 by short hairpin RNA significantly increased ABT-737-induced apoptosis.7 In this paper, we show that ARC induces potent apoptosis in human leukemia cells and that combination of sub-apoptotic (nanomolar) concentrations of ARC and ABT-737 stimulates very robust cell death in leukemia cell lines.

Two distinct pathways leading to cell death have been identified. First, the extrinsic pathway is initiated by death receptors, and second, the intrinsic pathway is initiated by the disruption of the mitochondrial membrane and accompanied by the release of cytochrome c. We found that ARC induces efficient apoptosis in leukemia cells after inhibition of caspase-8 (Figure 1c), suggesting that it induces intrinsic apoptosis. To confirm the fact that ARC-induced apoptosis in leukemia cells is linked to mitochondrial membrane depolarization, we treated CEM, HL-60, NB4 and U937 leukemia cells with either dimethyl sulfoxide or 1 μM of ARC. After 24 h, cells were loaded with TMRE (tetramethylrhodamine ethyl ester), a mitochondrial membrane potential indicator and sorted by fluorescence-activated cell sorting (FACS) analysis (Figure 1d). As shown in the Figure 1d, ARC treatment of leukemia cell lines led to a loss of mitochondrial membrane potential, as indicated by the shift to the left of the peak of TMRE fluorescence. These data suggest that administration of ARC promotes early mitochondrial damage in leukemia cells and they undergo ARC-induced apoptosis by the intrinsic pathway.

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Acknowledgements

We thank Dr Bulbul Pandit (University of Illinois at Chicago) for reading the manuscript and for her valuable comments. This work was supported by DOD CML Exploration—Hypothesis Development Award CM064025, Leukemia Research Foundation award and NIH grants 1RO1CA1294414-01A1 and 1R21CA134615-01 to ALG.

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  1. Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    U G Bhat & A L Gartel

  2. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA

    A L Gartel

  3. Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA

    A L Gartel

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  1. U G Bhat
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Correspondence to A L Gartel.

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Bhat, U., Gartel, A. Nucleoside analog ARC targets Mcl-1 to induce apoptosis in leukemia cells. Leukemia 24, 851–855 (2010). https://doi.org/10.1038/leu.2010.3

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