In:
Chemical Science, Royal Society of Chemistry (RSC), Vol. 13, No. 25 ( 2022), p. 7482-7491
Abstract:
Gramicidin A (1) is a linear 15-mer peptidic natural product. Because of its sequence of alternating d - and l -chirality, 1 folds into a β 6.3 -helix in a lipid bilayer and forms a head-to-head dimer to function as a transmembrane channel for monovalent cations (H + , Na + , and K + ). The potent anticancer activity of 1 was believed to be mainly attributed to the free ion diffusion across the plasma membrane. In this study, we investigated the cytostatic action of 1 in nanomolar concentrations using the human breast cancer cell line MCF-7, and revealed the unprecedented spatiotemporal behavior of 1 for the first time. Compound 1 not only disrupted the ion concentration gradients of the plasma membrane, but also localized in the mitochondria and depolarized the inner mitochondrial membrane. The diminished H + gradient in the mitochondria inhibited ATP synthesis. The resultant mitochondrial malfunction led to mitophagy, while the cellular energy depletion induced G1 phase accumulation. The multiple events occurred in a time-dependent fashion and ultimately caused potent inhibition of cell growth. The present study provides valuable information for the design and development of new cytostatic agents exploiting channel-forming natural products.
Type of Medium:
Online Resource
ISSN:
2041-6520
,
2041-6539
Language:
English
Publisher:
Royal Society of Chemistry (RSC)
Publication Date:
2022
detail.hit.zdb_id:
2559110-1
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