Translational cancer research · 2026
Glaucocalyxin A sensitizes ovarian cancer cells to PARP inhibitors by inducing DNA damage.
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Zhuang Lingling, Hu Lanyan, Chen Qi
Аннотация
BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) have demonstrated therapeutic advantages in ovarian cancer (OC) patients with homologous recombination (HR) deficiency. However, their effectiveness is limited in HR-proficient or acquired resistance tumors. Glaucocalyxin A (GLA) is an ent-kauranoid diterpene with anti-tumor properties. This study aimed to investigate the role and underlying mechanisms of GLA in OC and its potential as a sensitizing agent for PARPi.
METHODS: The anti-proliferative effect of GLA on OC cells was evaluated both in vitro and in vivo. RNA-sequencing (RNA-seq) was performed to identify GLA-regulated pathways. DNA damage and cell cycle progression were assessed by immunofluorescence, neutral comet assay, and flow cytometry. The expression and activation of key proteins in the DNA damage response (DDR), HR, and Fanconi anemia (FA) pathways were analyzed by western blotting and immunofluorescence. The synergistic effect of GLA combined with the PARPi talazoparib was evaluated in vitro and in SKOV3 xenografts.
RESULTS: GLA significantly inhibited OC cell proliferation in vitro and in vivo. RNA-seq analysis revealed that GLA induced G2/M cell cycle arrest and DNA damage. Mechanistically, GLA activated the ATM-Chk2 pathway while suppressing the ATR-Chk1 axis within the DDR. Furthermore, GLA inhibited HR and FA pathways, leading to DNA repair deficiency. Notably, a sequential regimen of GLA followed by talazoparib markedly increased drug responsiveness and DNA damage levels, and synergistically enhanced the anti-tumor effect of PARPi in SKOV3 xenografts.
CONCLUSIONS: This study identifies GLA as a potential PARPi-sensitizing agent and provides a preclinical rationale for sequential combination therapy to broaden the therapeutic utility of PARPi in HR-proficient OC.
METHODS: The anti-proliferative effect of GLA on OC cells was evaluated both in vitro and in vivo. RNA-sequencing (RNA-seq) was performed to identify GLA-regulated pathways. DNA damage and cell cycle progression were assessed by immunofluorescence, neutral comet assay, and flow cytometry. The expression and activation of key proteins in the DNA damage response (DDR), HR, and Fanconi anemia (FA) pathways were analyzed by western blotting and immunofluorescence. The synergistic effect of GLA combined with the PARPi talazoparib was evaluated in vitro and in SKOV3 xenografts.
RESULTS: GLA significantly inhibited OC cell proliferation in vitro and in vivo. RNA-seq analysis revealed that GLA induced G2/M cell cycle arrest and DNA damage. Mechanistically, GLA activated the ATM-Chk2 pathway while suppressing the ATR-Chk1 axis within the DDR. Furthermore, GLA inhibited HR and FA pathways, leading to DNA repair deficiency. Notably, a sequential regimen of GLA followed by talazoparib markedly increased drug responsiveness and DNA damage levels, and synergistically enhanced the anti-tumor effect of PARPi in SKOV3 xenografts.
CONCLUSIONS: This study identifies GLA as a potential PARPi-sensitizing agent and provides a preclinical rationale for sequential combination therapy to broaden the therapeutic utility of PARPi in HR-proficient OC.