1. Sulforaphane enhances the anticancer activity of taxanes against triple negative breast cancer by killing cancer stem cells
- Author
-
Lichao Sun, Shuhua Bai, Gi Lim, Joseph Burnett, Yasuhiro Tsume, Hayley J. Paholak, Ronak B. Shah, Duxin Sun, Rebekah Lim, Yanyan Li, Tao Zhang, Sean P. McDermott, and Max S. Wicha
- Subjects
0301 basic medicine ,Cancer Research ,Time Factors ,Transcription, Genetic ,Aldehyde dehydrogenase ,Triple Negative Breast Neoplasms ,Docetaxel ,Mice, SCID ,Pharmacology ,chemistry.chemical_compound ,0302 clinical medicine ,Isothiocyanates ,Mice, Inbred NOD ,Antineoplastic Combined Chemotherapy Protocols ,Triple-negative breast cancer ,biology ,Cell Death ,Chemistry ,Primary tumor ,Tubulin Modulators ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Phenotype ,Oncology ,Paclitaxel ,030220 oncology & carcinogenesis ,Sulfoxides ,Neoplastic Stem Cells ,Female ,Taxoids ,Inflammation Mediators ,medicine.drug ,Signal Transduction ,Transfection ,Article ,03 medical and health sciences ,Breast cancer ,NF-kappa B p52 Subunit ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Proliferation ,Dose-Response Relationship, Drug ,Interleukin-6 ,Interleukin-8 ,Transcription Factor RelA ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,biology.protein ,Cancer research ,Sulforaphane - Abstract
Triple negative breast cancer (TNBC) typically exhibits rapid progression, high mortality and faster relapse rates relative to other breast cancer subtypes. In this report we examine the combination of taxanes (paclitaxel or docetaxel) with a breast cancer stem cell (CSC)-targeting agent sulforaphane for use against TNBC. We demonstrate that paclitaxel or docetaxel treatment induces IL-6 secretion and results in expansion of CSCs in TNBC cell lines. Conversely, sulforaphane is capable of preferentially eliminating CSCs, by inhibiting NF-κB p65 subunit translocation, downregulating p52 and consequent downstream transcriptional activity. Sulforaphane also reverses taxane-induced aldehyde dehydrogenase-positive (ALDH+) cell enrichment, and dramatically reduces the size and number of primary and secondary mammospheres formed. In vivo in an advanced treatment orthotopic mouse xenograft model together with extreme limiting dilution analysis (ELDA), the combination of docetaxel and sulforaphane exhibits a greater reduction in primary tumor volume and significantly reduces secondary tumor formation relative to either treatment alone. These results suggest that treatment of TNBCs with cytotoxic chemotherapy would be greatly benefited by the addition of sulforaphane to prevent expansion of and eliminate breast CSCs.
- Published
- 2016