A dual-action niclosamide-based prodrug that targets cancer stem cells and inhibits TNBC metastasis.
Ji Hyeon KimSoeun ParkEunsun JungJinwoo ShinYoon-Jae KimJi Young KimJonathan L SesslerJae Hong SeoJong Seung KimPublished in: Proceedings of the National Academy of Sciences of the United States of America (2023)
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, CD44 high /CD24 low 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.
Keyphrases
- cancer stem cells
- cell cycle arrest
- cell proliferation
- induced apoptosis
- small cell lung cancer
- cell death
- free survival
- endoplasmic reticulum stress
- cancer therapy
- squamous cell carcinoma
- oxidative stress
- papillary thyroid
- gene expression
- poor prognosis
- lymph node
- transcription factor
- signaling pathway
- climate change
- immune response
- risk assessment
- vascular endothelial growth factor
- newly diagnosed
- nk cells
- inflammatory response
- long non coding rna
- nuclear factor