Tozasertib + cisplatin inhibits proliferation, migration, and induces apoptosis in esophageal carcinoma cells.

BACKGROUND

Esophageal cancer is a highly aggressive malignancy with limited treatment options. Cisplatin (CDDP)-based chemotherapy is often restricted by the development of drug resistance and systemic toxicity. Aurora kinase inhibitors have emerged as promising chemosensitizers in various cancers.

OBJECTIVE

It was to investigate the impact of the kinase inhibitor Tozasertib (VX-680) on the extracellular signal-regulated kinase (ERK) pathway and its synergistic mechanism with cisplatin (CDDP) in inducing senescence in esophageal cancer cells.

METHODS

Experiments were conducted using human esophageal cancer cell lines TE-1 and KYSE150, with the following groups: blank control, Tozasertib monotherapy, CDDP monotherapy, Tozasertib combined with CDDP, and a positive control group of CDDP + 5-fluorouracil (5-FU) (3 μM CDDP + 30 μM 5-fluorouracil). Cell proliferation, migration, and apoptosis, and protein levels of all groups were compared and analyzed.

RESULTS

Tozasertib + CDDP group (0.08 μM Tozasertib + 0.75 μg/mL CDDP) demonstrated significantly reduced cell proliferation rates (41.6% ± 2.9% in TE-1 cells and 38.2% ± 3.1% in KYSE150 cells) and migration rates (7.3% ± 1.8% in TE-1 and 8.5% ± 1.4% in KYSE150), with superior efficacy compared to monotherapy groups (P < 0.05). The Tozasertib + CDDP group exhibited the highest apoptosis rate at 48 h (TE-1: 44.6% ± 4.5%; KYSE150: 42.3% ± 4.4%, P < 0.05). Conditioned medium from the Tozasertib + CDDP group showed the strongest inhibitory effect on human umbilical vein endothelial cell (HUVEC) tube formation (total tube length: 3220 ± 401 pixels for TE-1-derived and 3390 ± 388 pixels for KYSE150-derived, P < 0.01). Western blot analysis revealed significant upregulation of cleaved PARP and cleaved caspase-3 (P < 0.05), along with marked downregulation of pro-caspase-3, phosphorylated ERK (p-ERK), matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor (VEGF), Cyclin B1, and c-Myc expression (P < 0.05) in the Tozasertib + CDDP group.

CONCLUSION

In summary, aurora kinase inhibitor combined with CDDP could suppress the ERK pathway to affect the biological process of esophageal carcinoma cells. Versus a simple drug, a drug combination could effectively inhibit the proliferation and migration of esophageal carcinoma cells, promote apoptosis, reduce angiogenesis, and induce cell cycle arrest.