Histone deacetylase (HDAC) inhibitors and doxorubicin combinations target both breast cancer stem cells and non-stem breast cancer cells simultaneously

  • Ling-Wei Hii
  • Felicia Fei-Lei Chung
  • Jaslyn Sian-Siu Soo
  • Boon Shing Tan
  • Chun-Wai Mai
  • Chee-Onn LeongEmail author
Preclinical study



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.


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.


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.


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


Breast cancer Cancer stem cells HDAC inhibitors Quisinostat Doxorubicin Drug combination 



This study was funded by the Malaysia Ministry of Education Exploratory Research Grant Scheme (LCO; ERGS/1/2013/SKK01/IMU/02/1) and Malaysia Ministry of Education Fundamental Grant Scheme (LCO; FRGS/1/2016/SKK08/IMU/01/1).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

10549_2019_5504_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 22 kb)
10549_2019_5504_MOESM2_ESM.pptx (1.1 mb)
Supplementary material 2 (PPTX 1110 kb). Supplementary Figure 1: Breast CSCs are intrinsically resistant to conventional chemotherapeutic agents. Both CSCs and non-CSCs derived from MDA-MB-468, MDA-MB-231, HCC38, and MCF-7 breast cancer cell lines were treated with cisplatin, doxorubicin and paclitaxel for 72 h. Points represent mean ± S.D. of at least three independent experiments. Supplemental Figure 2: Combinatory effects of HDACi and paclitaxel on MDA-MB-468 breast CSCs and non-CSCs. MDA-MB-468 breast CSCs and non-CSCs were treated with paclitaxel and/or HDACi for 72 h. Dose–response surface curves and synergy of each combination was assessed using the HSA model (effect-based approach), as implemented in Combenefit software [32]. Level of synergism (blue) or antagonism (red) at each concentration is represented by color scale bar. All experiments were conducted at least three times


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Authors and Affiliations

  1. 1.Department of Life Sciences, School of PharmacyInternational Medical UniversityBukit JalilMalaysia
  2. 2.School of Postgraduate Studies and ResearchInternational Medical UniversityBukit JalilMalaysia
  3. 3.Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE)International Agency for Research on Cancer World Health OrganizationLyon Cedex 08France
  4. 4.Cancer Research Malaysia, Sime Darby Medical CentreSubang JayaMalaysia
  5. 5.Institute of Biological ChemistryAcademia SinicaTaipeiTaiwan
  6. 6.Department of Pharmaceutical Chemistry, School of PharmacyInternational Medical UniversityBukit JalilMalaysia
  7. 7.Centre for Cancer and Stem Cell Research, Institute for Research, Development and InnovationInternational Medical UniversityBukit JalilMalaysia

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