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Synthesis and Characterization of Novel BMI1 Inhibitors Targeting Cellular Self-Renewal in Hepatocellular Carcinoma

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Abstract

Background

Hepatocellular carcinoma (HCC) represents one of the most lethal cancers worldwide due to therapy resistance and disease recurrence. Tumor relapse following treatment could be driven by the persistence of liver cancer stem-like cells (CSCs). The protein BMI1 is a member of the polycomb epigenetic factors governing cellular self-renewal, proliferation, and stemness maintenance. BMI1 expression also correlates with poor patient survival in various cancer types.

Objective

We aimed to elucidate the extent to which BMI1 can be used as a potential therapeutic target for CSC eradication in HCC.

Methods

We have recently participated in characterizing the first known pharmacological small molecule inhibitor of BMI1. Here, we synthesized a panel of novel BMI1 inhibitors and examined their ability to alter cellular growth and eliminate cancer progenitor/stem-like cells in HCC with different p53 backgrounds.

Results

Among various molecules examined, RU-A1 particularly downregulated BMI1 expression, impaired cell viability, reduced cell migration, and sensitized HCC cells to 5-fluorouracil (5-FU) in vitro. Notably, long-term analysis of HCC survival showed that, unlike chemotherapy, RU-A1 effectively reduced CSC content, even as monotherapy. BMI1 inhibition with RU-A1 diminished the number of stem-like cells in vitro more efficiently than the model compound C-209, as demonstrated by clonogenic assays and impairment of CSC marker expression. Furthermore, xenograft assays in zebrafish showed that RU-A1 abrogated tumor growth in vivo.

Conclusions

This study demonstrates the ability to identify agents with the propensity for targeting CSCs in HCC that could be explored as novel treatments in the clinical setting.

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Acknowledgements

We thank Leonard Zon (Harvard University) for the Casper zebrafish. We thank members of Dr. David Augeri’s laboratory and core facilities at the Molecular Design and Synthesis laboratory, Rutgers Translational Sciences at Rutgers University for the synthesis, purification and mass spectral analyses of the small molecules utilized in this study.

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Author notes

  1. Monica Bartucci and Mohamed S. Hussein contributed equally to this work

Authors and Affiliations

  1. Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA

    Monica Bartucci, Mohamed S. Hussein, Eric Huselid, Kathleen Flaherty, Michele Patrizii, Saurabh V. Laddha, S. David Kimball, David J. Augeri & Hatem E. Sabaawy

  2. Clinical and Chemical Pathology, National Research Centre, Cairo, Egypt

    Mohamed S. Hussein & Mona A. M. Awad

  3. Graduate Program in Cellular and Molecular Pharmacology, Graduate School of Biomedical Sciences, Rutgers University, New Brunswick, NJ, 08901, USA

    Eric Huselid, Michele Patrizii & Hatem E. Sabaawy

  4. Graduate Program in Quantitative Biomedicine, Institute for Quantitative Biomedicine at Rutgers University, New Brunswick, NJ, 08901, USA

    Saurabh V. Laddha

  5. Molecular Design and Synthesis Laboratory, Rutgers Translational Sciences, Rutgers University, Piscataway, NJ, 08854, USA

    Cindy Kui, Rachel A. Bigos, John A. Gilleran, S. David Kimball & David J. Augeri

  6. Department of Medicinal Chemistry, EMSOP, Rutgers University, Piscataway, NJ, 08854, USA

    Cindy Kui, Rachel A. Bigos, John A. Gilleran, S. David Kimball & David J. Augeri

  7. Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt

    Mervat M. S. El Ansary

  8. Department of Medicine, RBHS-Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 08901, USA

    Hatem E. Sabaawy

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  1. Monica Bartucci
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  2. Mohamed S. Hussein
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  11. Mona A. M. Awad
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  14. Hatem E. Sabaawy
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Corresponding author

Correspondence to Hatem E. Sabaawy.

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Funding for the Study

This project was supported by the Department of Defense Grant (W81XWH-12-1-0249 to H.S.), National Cancer Institute (P30 CA072720 to R.D.) and New Jersey Health Foundation award (Research grant PC-72-16 to H.S.).

Conflict of Interest

The authors declare no conflict of interest.

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Bartucci, M., Hussein, M.S., Huselid, E. et al. Synthesis and Characterization of Novel BMI1 Inhibitors Targeting Cellular Self-Renewal in Hepatocellular Carcinoma. Targ Oncol 12, 449–462 (2017). https://doi.org/10.1007/s11523-017-0501-x

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