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A Small Molecule Strategy for Targeting Cancer Stem Cells in Hypoxic Microenvironments and Preventing Tumorigenesis

Authors
Kim, Ji HyeonVerwilst, PeterWon, MiaeLee, JunhyoungSessler, Jonathan L.Han, JiyouKim, Jong Seung
Issue Date
8-9월-2021
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.143, no.35, pp.14115 - 14124
Indexed
SCIE
SCOPUS
Journal Title
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume
143
Number
35
Start Page
14115
End Page
14124
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/136375
DOI
10.1021/jacs.1c03875
ISSN
0002-7863
Abstract
Breast cancer consists of heterogenic subpopulations, which determine the prognosis and response to chemotherapy. Among these subpopulations, a very limited number of cancer cells are particularly problematic. These cells, known as breast cancer stem cells (BCSCs), are thought responsible for metastasis and recurrence. They are thus major contributor to the unfavorable outcomes seen for many breast cancer patients. BCSCs are more prevalent in the hypoxic niche. This is an oxygen-deprived environment that is considered crucial to their proliferation, stemness, and self-renewal but also one that makes BCSCs highly refractory to traditional chemotherapeutic regimens. Here we report a small molecule construct, AzCDF, that allows the therapeutic targeting of BCSCs and which is effective in normally refractory hypoxic tumor environments. A related system, AzNap, has been developed that permits CSC imaging. Several design elements are incorporated into AzCDF, including the CAIX inhibitor acetazolamide (Az) to promote localization in MDA-MB-231 CSCs, a dimethylnitrothiophene subunit as a hypoxia trigger, and a 3,4-difluorobenzylidene curcumin (CDF) as a readily released therapeutic payload. This allows AzCDF to serve as a hypoxia-liable molecular platform that targets BCSCs selectively which decreases CSC migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a CSC-targeting small molecule has been shown to prevent tumorigenesis in an animal model.
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