A dual-action niclosamide-based prodrug that targets cancer stem cells and inhibits TNBC metastasis

Ji Hyeon Kim, Soeun Park, Eunsun Jung, Jinwoo Shin, Yoon Jae Kim, Ji Young Kim, Jonathan L. Sessler, Jae Hong Seo, Jong Seung Kim

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Chemotherapy typically destroys the tumor mass but rarely eradicates the cancer stem cells (CSCs) that can drive metastatic recurrence. A key current challenge is finding ways to eradicate CSCs and suppress their characteristics. Here, we report a prodrug, Nic-A, created by combining a carbonic anhydrase IX (CAIX) inhibitor, acetazolamide, with a signal transducer and transcriptional activator 3 (STAT3) inhibitor, niclosamide. Nic-A was designed to target triple-negative breast cancer (TNBC) CSCs and was found to inhibit both proliferating TNBC cells and CSCs via STAT3 dysregulation and suppression of CSC-like properties. Its use leads to a decrease in aldehyde dehydrogenase 1 activity, CD44high/CD24low stem-like subpopulations, and tumor spheroid-forming ability. TNBC xenograft tumors treated with Nic-A exhibited decreased angiogenesis and tumor growth, as well as decreased Ki-67 expression and increased apoptosis. In addition, distant metastases were suppressed in TNBC allografts derived from a CSC-enriched population. This study thus highlights a potential strategy for addressing CSC-based cancer recurrence.

Original languageEnglish
Article numbere2304081120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number21
DOIs
Publication statusPublished - 2023 May 23

Bibliographical note

Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

ASJC Scopus subject areas

  • General

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