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.

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

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发表日期：

2026年4月27日

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Chunqin Tian,
Lichun Cui,
Xiaoyan Wang

摘要

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.