Monica Bartucci1, Mohamed S Hussein1,2, Eric Huselid1,3, Kathleen Flaherty1, Michele Patrizii1,3, Saurabh V Laddha1,4, Cindy Kui5,6, Rachel A Bigos5,6, John A Gilleran5,6, Mervat M S El Ansary7, Mona A M Awad2, S David Kimball1,5,6, David J Augeri1,5,6, Hatem E Sabaawy8,9,10. 1. Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA. 2. Clinical and Chemical Pathology, National Research Centre, Cairo, Egypt. 3. Graduate Program in Cellular and Molecular Pharmacology, Graduate School of Biomedical Sciences, Rutgers University, New Brunswick, NJ, 08901, USA. 4. Graduate Program in Quantitative Biomedicine, Institute for Quantitative Biomedicine at Rutgers University, New Brunswick, NJ, 08901, USA. 5. Molecular Design and Synthesis Laboratory, Rutgers Translational Sciences, Rutgers University, Piscataway, NJ, 08854, USA. 6. Department of Medicinal Chemistry, EMSOP, Rutgers University, Piscataway, NJ, 08854, USA. 7. Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt. 8. Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, 08901, USA. sabaawhe@cinj.rutgers.edu. 9. Graduate Program in Cellular and Molecular Pharmacology, Graduate School of Biomedical Sciences, Rutgers University, New Brunswick, NJ, 08901, USA. sabaawhe@cinj.rutgers.edu. 10. Department of Medicine, RBHS-Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, 08901, USA. sabaawhe@cinj.rutgers.edu.
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.
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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