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Metallo-supramolecular Complexes Enantioselectively Eradicate Cancer Stem Cells in Vivo
- Qin, Hongshuang, Zhao, Chuanqi, Sun, Yuhuan, Ren, Jinsong, Qu, Xiaogang
- Journal of the American Chemical Society 2017 v.139 no.45 pp. 16201-16209
- DNA, DNA damage, apoptosis, breasts, carcinogenesis, cell growth, drug design, drug resistance, drugs, enantiomers, enantioselectivity, enzyme activity, ligands, metastasis, neoplasm cells, neoplasms, stem cells, telomerase, telomeres
- Cancer stem cells (CSCs) are responsible for drug resistance, metastasis and recurrence of cancers. However, there is still no clinically approved drug that can effectively eradicate CSCs. Thus, it is crucial and important to develop specific CSC-targeting agents. Chiral molecular recognition of DNA plays an important role in rational drug design. Among them, polymorphic telomeric G-quadruplex DNA has received much attention due to its significant roles in telomerase activity and chromosome stability. Herein, we find that one enantiomer of zinc-finger-like chiral metallohelices, [Ni₂L₃]⁴⁺-P, a telomeric G-quadruplex-targeting ligand, can preferentially reduce cell growth in breast CSCs compared to the bulk cancer cells. In contrast, its enantiomer, [Ni₂L₃]⁴⁺-M, has little effect on both populations. Further studies indicate that [Ni₂L₃]⁴⁺-P can repress CSC properties and induce apoptosis in breast CSCs. This is different to the bulk cancer cells. The inhibition of breast CSC traits is involved in the nuclear translocation of hTERT. The apoptosis is associated with the induction of telomere uncapping, telomere DNA damage and the degradation of 3′-overhang. Moreover, [Ni₂L₃]⁴⁺-P, but not [Ni₂L₃]⁴⁺-M, has the ability to reduce tumorigenesis of breast CSCs in vivo. To our knowledge, this is the first report that chiral complexes show significant enantioselectivity on eradicating CSCs.