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06.06.2017 | Original Research Article

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

verfasst von: Monica Bartucci, Mohamed S. Hussein, Eric Huselid, Kathleen Flaherty, Michele Patrizii, Saurabh V. Laddha, Cindy Kui, Rachel A. Bigos, John A. Gilleran, Mervat M. S. El Ansary, Mona A. M. Awad, S. David Kimball, David J. Augeri, Hatem E. Sabaawy

Erschienen in: Targeted Oncology | Ausgabe 4/2017

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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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Titel: Synthesis and Characterization of Novel BMI1 Inhibitors Targeting Cellular Self-Renewal in Hepatocellular Carcinoma
verfasst von: Monica Bartucci
Mohamed S. Hussein
Eric Huselid
Kathleen Flaherty
Michele Patrizii
Saurabh V. Laddha
Cindy Kui
Rachel A. Bigos
John A. Gilleran
Mervat M. S. El Ansary
Mona A. M. Awad
S. David Kimball
David J. Augeri
Hatem E. Sabaawy
Publikationsdatum: 06.06.2017
Verlag: Springer International Publishing
Erschienen in: Targeted Oncology / Ausgabe 4/2017
Print ISSN: 1776-2596
Elektronische ISSN: 1776-260X
DOI: https://doi.org/10.1007/s11523-017-0501-x

Springer Medizin

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