Synergistic effect of inhibiting CHK2 and DNA replication on cancer cell growth

Abstract

Abstract Cancer cells display high levels of oncogene-induced replication stress (RS) and rely on DNA damage checkpoint for viability. This feature is exploited by cancer therapies to either increase RS to unbearable levels or to inhibit checkpoint kinases involved in the DNA damage response (DDR). Thus far, treatments that combine these two strategies have shown promise but also have severe adverse effects. To identify novel, better-tolerated anticancer combinations, we screened a collection of plant extracts and found two natural compounds from the same plant, Psoralea corylifolia, that synergistically inhibit proliferation of cancer cells. Bakuchiol inhibited DNA replication in human cells and in Xenopus egg extracts, and activated the checkpoint kinase CHK1, likely by targeting DNA polymerases. Isobavachalcone interfered with DNA double-strand breaks (DSBs) repair by inhibiting the checkpoint kinase CHK2 and the resection of DNA ends. The combination of isobavachalcone and bakuchiol synergistically inhibited cancer cell proliferation in vitro. Importantly, it also prevented tumor development in xenografted mice at the concentration ratio naturally found in plant extracts. The synergistic effect of inhibiting DNA replication and resection identifies a novel vulnerability of cancer cells that might be exploited by using clinically approved inhibitors of these mechanisms in novel combination therapies.