Affiliations 

  • 1 Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
  • 2 Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE), International Agency for Research on Cancer World Health Organization, 150 Cours Albert Thomas, 69372, Lyon Cedex 08, France
  • 3 Cancer Research Malaysia, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia
  • 4 Institute of Biological Chemistry, Academia Sinica, 128, Academia Road Sec. 2, Nankang, Taipei, 115, Taiwan
  • 5 Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
  • 6 Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia. cheeonn_leong@imu.edu.my
Breast Cancer Res Treat, 2020 Feb;179(3):615-629.
PMID: 31784862 DOI: 10.1007/s10549-019-05504-5

Abstract

PURPOSE: Breast cancer stem cells (CSCs) are a small subpopulation of cancer cells that have high capability for self-renewal, differentiation, and tumor initiation. CSCs are resistant to chemotherapy and radiotherapy, and are responsible for cancer recurrence and metastasis.

METHODS: By utilizing a panel of breast cancer cells and mammospheres culture as cell-based screening platforms, we performed high-throughput chemical library screens to identify agents that are effective against breast CSCs and non-CSCs. The hit molecules were paired with conventional chemotherapy to evaluate the combinatorial treatment effects on breast CSCs and non-CSCs.

RESULTS: We identified a total of 193 inhibitors that effectively targeting both breast CSCs and non-CSCs. We observed that histone deacetylase inhibitors (HDACi) synergized conventional chemotherapeutic agents (i.e., doxorubicin and cisplatin) in targeting breast CSCs and non-CSCs simultaneously. Further analyses revealed that quisinostat, a potent inhibitor for class I and II HDACs, potentiated doxorubicin-induced cytotoxicity in both breast CSCs and non-CSCs derived from the basal-like (MDA-MB-468 and HCC38), mesenchymal-like (MDA-MB-231), and luminal-like breast cancer (MCF-7). It was also observed that the basal-like breast CSCs and non-CSCs were more sensitive to the co-treatment of quisinostat with doxorubicin compared to that of the luminal-like breast cancer subtype.

CONCLUSION: In conclusion, this study demonstrates the potential of HDACi as therapeutic options, either as monotherapy or in combination with chemotherapeutics against refractory breast cancer.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.