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

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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Funding

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).

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Authors and Affiliations

  1. Department of Life Sciences, School of Pharmacy, International Medical University, No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia

    Ling-Wei Hii & Chee-Onn Leong

  2. School of Postgraduate Studies and Research, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia

    Ling-Wei Hii

  3. 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

    Felicia Fei-Lei Chung

  4. Cancer Research Malaysia, Sime Darby Medical Centre, Subang Jaya, Selangor, Malaysia

    Jaslyn Sian-Siu Soo

  5. Institute of Biological Chemistry, Academia Sinica, 128, Academia Road Sec. 2, Nankang, Taipei, 115, Taiwan

    Boon Shing Tan

  6. Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia

    Chun-Wai Mai

  7. Centre for Cancer and Stem Cell Research, Institute for Research, Development and Innovation, International Medical University, 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia

    Chun-Wai Mai & Chee-Onn Leong

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  1. Ling-Wei Hii
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Correspondence to Chee-Onn Leong.

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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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Hii, LW., Chung, F.FL., Soo, J.SS. et al. Histone deacetylase (HDAC) inhibitors and doxorubicin combinations target both breast cancer stem cells and non-stem breast cancer cells simultaneously. Breast Cancer Res Treat 179, 615–629 (2020). https://doi.org/10.1007/s10549-019-05504-5

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  • DOI: https://doi.org/10.1007/s10549-019-05504-5

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