Borneol exerts an enhanced anti-tumor effect on triple-negative breast cancer by targeting PTGS2 to reinforce gemcitabine-induced DNA damage.

OBJECTIVES: Borneol has anti-inflammatory and sensitizing effects, but its influence on the sensitivity of triple-negative breast cancer (TNBC) to gemcitabine (GEM) chemotherapy remains unclear. This study aimed to investigate the chemosensitizing effect of borneol on GEM in TNBC and clarify its underlying molecular mechanism.

METHODS: The anti-tumor effects of borneol combined with GEM were evaluated in 4 T1 and MDA-MB-231 cells, and in tumor-bearing mice. Cell proliferation and apoptosis were examined. DNA damage was assessed by detecting γ-H2AX and ATM/ATR/CHK1/CHK2 phosphorylation. The direct target of borneol, prostaglandin-endoperoxide synthase 2 (PTGS2), was screened and verified through bioinformatics, CETSA, and DARTS-WB, and its role was validated by PTGS2 overexpression experiments.

KEY FINDINGS: Borneol alone exhibited anti-tumor and pro-apoptotic effects. Combined with GEM, it substantially enhanced anti-tumor efficacy, induced DNA damage, activated the ATM/ATR-CHK1/CHK2 pathway, and increased GEM sensitivity in TNBC cells. Mechanistically, PTGS2 was identified as a key target, and borneol directly bound to PTGS2 and downregulated its expression. PTGS2 overexpression could partially reverse the sensitizing effect of borneol on GEM and its DNA damage-inducing effect.

CONCLUSIONS: Borneol enhances the anti-tumor effect of GEM on TNBC by directly binding to PTGS2 and downregulating PTGS2 expression, thereby activating the ATM/ATR-CHK1/CHK2 pathway, intensifying DNA damage in TNBC cells, and promoting tumor cell apoptosis.