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Proc. Natl. Acad. Sci. USA, May 15, 2023 | https://doi.org/10.1073/pnas.2304081120 A dual-action niclosamide-based prodrug that targets cancer stem cells and inhibits TNBC metastasis

Ji Hyeon Kim ^a,1, Soeun Park ^b,c,d,1, Eunsun Jung ^b,c,d, Jinwoo Shin ^a, Yoon-Jae Kim ^b,c,d,2, Ji Young Kim ^b,c,d,2, Jonathan L. Sessler ^e,2, Jae Hong Seo ^b,c,d,2, and Jong Seung Kim ^a,2

^aDepartment of Chemistry, Korea University, Seoul 02841, Korea;
^bDivision of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Korea;
^cBrain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Korea;
^dDepartment of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 08308, Korea;
^eDepartment of Chemistry, The University of Texas at Austin, Austin, TX 78712-1224

¹Equally contributed as the author.
²Corresponding authors: Correspondence to Yoon-Jae Kim, Ji Young Kim, Jonathan L. Sessler, Jae Hong Seo or Jong Seung Kim.

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.

논문정보

형식Research article
게재일2023년 05월 (BRIC 등록일 2023-05-23)
연구진국내(교신)+국외 연구진
분야 의약학 > 종양의학

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