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Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis

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Summary

Two novel dichlorophenyl urea compounds, SR4 and SR9, were synthesized in our laboratory and evaluated for anti-cancer activities. Specifically, we investigated the antiproliferative properties of these new compounds on promyelocytic HL-60 leukemia cells by analyzing their effects on cell differentiation, cell cycle progression and apoptosis. SR4 and SR9 were both cytototoxic to HL-60 cells in a dose-and time-dependent manner, with IC50 of 1.2 μM and 2.2 μM, respectively, after 72 h treatment. Both compounds strongly suppressed growth of HL-60 cells by promoting cell cycle arrest at the G0/G1 transition, with concomitant decrease in protein levels of cyclins D1 and E2 and cyclin-dependent kinases (CDK 2 and CDK 4), and increased protein expression of CDK inhibitors p21WAF1/Cip1 and p27Kip1. In addition, either compounds induce cell differentiation as detected by increased NBT staining and expression of CD11b and CD14. Treatment with SR compounds also promoted mitochondrial-dependent apoptosis as confirmed by Annexin V-FITC double staining, DNA fragmentation, increased expression of caspase 3, 7 and 9, cytochrome c release, PARP degradation, and collapse in mitochondrial membrane potential (ΔΨMT). Collectively, these results provide evidence that SR4 and SR9 have the potential for the treatment of human leukemia and merit further investigation as therapeutic agents against other types of cancer.

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Acknowledgments

The authors are grateful to Jacquelin and Isaac Moradi for their many years of support and research funding. We are also thankful to Mariko Lee and Dr. Brian Armstrong (Microscope Core Lab, COH) and Lucy Brown (Analytical Core Facility, COH) for their technical assistance in microscopy and flow cytometry analyses, respectively.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Diabetes, Endocrinology and Metabolism, Beckman Research Institute of the City of Hope National Medical Center, Duarte, CA, 91010, USA

    James L. Figarola, Yehua Weng & Samuel Rahbar

  2. Center for Translational Medicinal Chemistry, Beckman Research Institute of the City of Hope National Medical Center, Duarte, CA, 91010, USA

    Christopher Lincoln

  3. Department of Molecular Medicine, Beckman Research Institute of the City of Hope National Medical Center, Duarte, CA, 91010, USA

    David Horne

Authors
  1. James L. Figarola
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  2. Yehua Weng
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  3. Christopher Lincoln
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  4. David Horne
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  5. Samuel Rahbar
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Corresponding author

Correspondence to James L. Figarola.

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Supplement Fig. 1

SR compounds inhibit growth and proliferation of human leukemia, lung and breast cancer cells. Cancer cells were exposed to various concentrations of SR compounds for 72 h, followed by determination of cell viability using the MTT (leukemia cells) or XTT assay (A-549, MCF-7 and MDA-MB-231 cells). Data expressed as mean ± SE from 3–4 independent experiments. (EPS 1753 kb)

Supplement Fig. 2

NIH/NCI 60 DTP Human Tumor Cell Lines five-dose growth response curve data for SR4. (EPS 2652 kb)

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Figarola, J.L., Weng, Y., Lincoln, C. et al. Novel dichlorophenyl urea compounds inhibit proliferation of human leukemia HL-60 cells by inducing cell cycle arrest, differentiation and apoptosis. Invest New Drugs 30, 1413–1425 (2012). https://doi.org/10.1007/s10637-011-9711-8

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  • DOI: https://doi.org/10.1007/s10637-011-9711-8

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