TY - JOUR
T1 - A Small Molecule Strategy for Targeting Cancer Stem Cells in Hypoxic Microenvironments and Preventing Tumorigenesis
AU - Kim, Ji Hyeon
AU - Verwilst, Peter
AU - Won, Miae
AU - Lee, Junhyoung
AU - Sessler, Jonathan L.
AU - Han, Jiyou
AU - Kim, Jong Seung
N1 - Funding Information:
This work was supported by the Korean Creative Research Initiative (CRI Project No. 2018R1A3B1052702, J.S.K.) and the Basic Science Research Programs (No. 2018R1A2B6002275, J.H.), and the Global PhD Fellowship (GPF) Program (No. 2019H1A2A1074096, J.H.K.) from the National Research Foundation of Korea (NRF) funded by the Korea Ministry of Science and ICT (MSIT). We also gratefully acknowledge support from Korea University and Hyupsung University. Initial support for the work in Austin came from the National Institutes of Health (CA 68682 to J.L.S.) with subsequent funding from the Robert A. Welch Foundation (F-0018 to J.L.S.).
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/9/8
Y1 - 2021/9/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114022765&partnerID=8YFLogxK
U2 - 10.1021/jacs.1c03875
DO - 10.1021/jacs.1c03875
M3 - Article
C2 - 34374290
AN - SCOPUS:85114022765
VL - 143
SP - 14115
EP - 14124
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 35
ER -
