Ebastine impairs metastatic spread in triple-negative breast cancer by targeting focal adhesion kinase.
Juyeon SeoMinsu ParkDongmi KoSeongjae KimJung Min ParkSoeun ParkKee Dal NamLee FarrandJinsol YangChaok SeokEunsun JungYoon-Jae KimJi Young KimJae Hong SeoPublished in: Cellular and molecular life sciences : CMLS (2023)
We sought to investigate the utility of ebastine (EBA), a second-generation antihistamine with potent anti-metastatic properties, in the context of breast cancer stem cell (BCSC)-suppression in triple-negative breast cancer (TNBC). EBA binds to the tyrosine kinase domain of focal adhesion kinase (FAK), blocking phosphorylation at the Y397 and Y576/577 residues. FAK-mediated JAK2/STAT3 and MEK/ERK signaling was attenuated after EBA challenge in vitro and in vivo. EBA treatment induced apoptosis and a sharp decline in the expression of the BCSC markers ALDH1, CD44 and CD49f, suggesting that EBA targets BCSC-like cell populations while reducing tumor bulk. EBA administration significantly impeded BCSC-enriched tumor burden, angiogenesis and distant metastasis while reducing MMP-2/-9 levels in circulating blood in vivo. Our findings suggest that EBA may represent an effective therapeutic for the simultaneous targeting of JAK2/STAT3 and MEK/ERK for the treatment of molecularly heterogeneous TNBC with divergent profiles. Further investigation of EBA as an anti-metastatic agent for the treatment of TNBC is warranted.
Keyphrases
- tyrosine kinase
- small cell lung cancer
- induced apoptosis
- signaling pathway
- squamous cell carcinoma
- pi k akt
- cell migration
- cell proliferation
- poor prognosis
- oxidative stress
- epidermal growth factor receptor
- long non coding rna
- protein kinase
- combination therapy
- drug delivery
- cell therapy
- nk cells
- cancer therapy
- pseudomonas aeruginosa