Bisdemethoxycurcumin disrupts Chk1-associated DNA damage checkpoint signaling and induces apoptosis in nasopharyngeal carcinoma cells

Curcuminoids have been widely explored for their diverse bioactivities, including antioxidant, anti-inflammatory, and antitumor effects. Among them, bisdemethoxycurcumin (BDMC) has been reported to suppress tumor proliferation and metastasis in several cancer types. However, the molecular mechanisms underlying the effects of BDMC in nasopharyngeal carcinoma (NPC) remain unclear. The effects of BDMC on apoptosis, cell-cycle progression, DNA damage, and Chk1 activity were examined using immunoblotting, flow cytometry, immunocytochemistry, and cellular thermal shift assay (CETSA). Molecular docking and molecular dynamics simulations were performed using BIOVIA Discovery Studio 2024. Our results demonstrated that BDMC exerted cytotoxic effects by inducing both intrinsic and extrinsic apoptotic pathways in NPC cells. c-Jun N-terminal kinase (JNK) signaling was involved in apoptotic induction through suppression of JNK phosphorylation. In parallel, BDMC directly engaged checkpoint kinase 1 (Chk1) and inhibited its phosphorylation. Chk1 inhibition by BDMC led to disruption of checkpoint control, S- and G2/M-phase arrest, and accumulation of DNA damage, accompanied by a distinct inactivation of Chk1 phosphorylation without alteration of total Chk1 protein expression. Notably, CHEK1 silencing did not significantly alter BDMC-induced caspase activation or apoptosis, whereas inhibition of caspase-dependent apoptosis with Z-VAD did not affect BDMC-induced γH2AX accumulation. These findings suggest that the apoptotic response and the Chk1-associated DNA damage response induced by BDMC are functionally separable under the conditions examined. This study reveals that the antitumor effects of BDMC involve distinct modulation of JNK-associated apoptotic signaling and Chk1-mediated checkpoint dysfunction. These findings provide mechanistic insight into BDMC-induced cytotoxicity and support its potential as a lead compound for further pharmacological investigation in NPC.