Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells

Sulaiman, Andrew; McGarry, Sarah; Chambers, Jason; Al-Kadi, Emil; Phan, Alexandra; Li, Li; Mediratta, Karan; Dimitroulakos, Jim; Addison, Christina; Li, Xuguang; Wang, Lisheng

doi:10.3390/ijms21165788

Submit to this Journal Review for this Journal Edit a Special Issue

Article Menu

...

Open AccessArticle

Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells

^1,2,3,†,

^1,2,†,

¹,

¹,

¹,

^1,2,

¹,

^1,4,

^1,4,

^1,5 and

^1,2,6,*

Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada

Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada

Department of Basic Science, Kansas City University of Medicine and Bioscience, 1750 Independence Ave, Kansas City, MO 64106, USA

⁴

Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada

⁵

Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Sir Frederick G. Banting Research Centre, 251 Sir Frederick Banting Driveway, Ottawa, ON K1A 0K9, Canada

⁶

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada

Author to whom correspondence should be addressed.

^†

These authors contributed equally.

Int. J. Mol. Sci. 2020, 21(16), 5788; https://doi.org/10.3390/ijms21165788

Received: 21 July 2020 / Revised: 6 August 2020 / Accepted: 10 August 2020 / Published: 12 August 2020

(This article belongs to the Special Issue Breast Cancer: From Pathophysiology to Novel Therapeutic Approaches)

View Full-Text Download PDF

Browse Figures

Review Reports Citation Export

Abstract

Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that, in turn, promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report we analyzed clinical datasets of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We, thus, developed a new therapeutic approach to inhibit EGFR and hypoxia by combination treatment with metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24− and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic; this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC. View Full-Text

Keywords: triple negative breast cancer; cancer stem cell; hypoxia; EGFR; cisplatin; PDX

▼ Show Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Supplementary Material

Supplementary File 1:
PDF-Document (PDF, 2297 KiB)

Share and Cite

MDPI and ACS Style

Sulaiman, A.; McGarry, S.; Chambers, J.; Al-Kadi, E.; Phan, A.; Li, L.; Mediratta, K.; Dimitroulakos, J.; Addison, C.; Li, X.; Wang, L. Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells. Int. J. Mol. Sci. 2020, 21, 5788. https://doi.org/10.3390/ijms21165788

AMA Style

Sulaiman A, McGarry S, Chambers J, Al-Kadi E, Phan A, Li L, Mediratta K, Dimitroulakos J, Addison C, Li X, Wang L. Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells. International Journal of Molecular Sciences. 2020; 21(16):5788. https://doi.org/10.3390/ijms21165788

Chicago/Turabian Style

Sulaiman, Andrew, Sarah McGarry, Jason Chambers, Emil Al-Kadi, Alexandra Phan, Li Li, Karan Mediratta, Jim Dimitroulakos, Christina Addison, Xuguang Li, and Lisheng Wang. 2020. "Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells" International Journal of Molecular Sciences 21, no. 16: 5788. https://doi.org/10.3390/ijms21165788

Find Other Styles

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Abstract views Pdf views Html views

Article Menu

Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells

Abstract

Supplementary Material

Share and Cite

Article Metrics

Article Access Statistics

Article Access Map by Country/Region

Further Information

Guidelines

MDPI Initiatives

Follow MDPI