TY - JOUR
T1 - Induction of Aryl Hydrocarbon Receptor-Mediated Cancer Cell-Selective Apoptosis in Triple-Negative Breast Cancer Cells by a High-Affinity Benzimidazoisoquinoline
AU - Elson, Daniel J.
AU - Nguyen, Bach D.
AU - Bernales, Sebastian
AU - Chakravarty, Sarvajit
AU - Jang, Hyo Sang
AU - Korjeff, Nicholas A.
AU - Zhang, Yi
AU - Wilferd, Sierra F.
AU - Castro, David J.
AU - Plaisier, Christopher L.
AU - Finlay, Darren
AU - Oshima, Robert G.
AU - Kolluri, Siva K.
N1 - Publisher Copyright:
© 2023 American Chemical Society.
PY - 2023/7/14
Y1 - 2023/7/14
N2 - Triple-negative breast cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses. In certain cancers, AhR activation by select small molecules induces cell cycle arrest or apoptosis via activation of tumor-suppressive transcriptional programs. AhR is expressed in triple-negative breast cancers, presenting a tractable therapeutic opportunity. Here, we identify a novel ligand of the aryl hydrocarbon receptor that potently and selectively induces cell death in triple-negative breast cancer cells and TNBC stem cells via the AhR. Importantly, we found that this compound, Analog 523, exhibits minimal cytotoxicity against multiple normal human primary cells. Analog 523 represents a high-affinity AhR ligand with potential for future clinical translation as an anticancer agent.
AB - Triple-negative breast cancer (TNBC) remains a disease with a paucity of targeted treatment opportunities. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is involved in a wide range of physiological processes, including the sensing of xenobiotics, immune function, development, and differentiation. Different small-molecule AhR ligands drive strikingly varied cellular and organismal responses. In certain cancers, AhR activation by select small molecules induces cell cycle arrest or apoptosis via activation of tumor-suppressive transcriptional programs. AhR is expressed in triple-negative breast cancers, presenting a tractable therapeutic opportunity. Here, we identify a novel ligand of the aryl hydrocarbon receptor that potently and selectively induces cell death in triple-negative breast cancer cells and TNBC stem cells via the AhR. Importantly, we found that this compound, Analog 523, exhibits minimal cytotoxicity against multiple normal human primary cells. Analog 523 represents a high-affinity AhR ligand with potential for future clinical translation as an anticancer agent.
KW - apoptosis
KW - aryl hydrocarbon receptor
KW - benzimidazoisoquinoline
KW - breast cancer stem cells
KW - triple-negative breast cancer
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U2 - 10.1021/acsptsci.2c00253
DO - 10.1021/acsptsci.2c00253
M3 - Article
AN - SCOPUS:85163412081
SN - 2575-9108
VL - 6
SP - 1028
EP - 1042
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 7
ER -