Selective killing of ALT-cancer cells by Withaferin-A involves destabilization of Rad51 and disruption of DNA repair.

ABSTRACT: Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism active in a subset of aggressive cancers. Targeting ALT remains a therapeutic challenge due to its complexity and lack of clinically specific inhibitors. Here, we report that the natural compound Withaferin A (Wi-A) selectively impairs ALT cancer cell viability by disrupting Rad51-dependent homologous recombination (HR), a critical pathway for resolving telomeric replication stress and DNA damage in ALT cells. Comparative analysis using isogenic ALT and telomerase-positive cells revealed that Wi-A selectively downregulates PI3K/AKT signaling and induces replication stress, telomeric DNA damage, and DNA repair deficiency in ALT cells. Mechanistically, Wi-A destabilizes the Rad51 nucleoprote

SUBMITTER: Yu Y 

PROVIDER: S-EPMC13649652 | biostudies-literature | 2026 Jul

REPOSITORIES: biostudies-literature