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Anticancer Agent Ukrain and Bortezomib Combination is Synergistic in 4T1 Breast Cancer Cells

硼替佐米 依托泊苷 细胞凋亡 顺铂 细胞毒性T细胞 癌细胞 细胞毒性 DNA断裂 化学 药理学 癌症研究 程序性细胞死亡 癌症 生物 医学 免疫学 化疗 体外 生物化学 内科学 多发性骨髓瘤
作者
Bircan Savran,Azmi Yerlikaya,Elif Erdoğan,Osman Genç
出处
期刊:Anti-cancer Agents in Medicinal Chemistry [Bentham Science]
卷期号:14 (3): 466-472 被引量:6
标识
DOI:10.2174/18715206113139990318
摘要

The identification and in-depth understanding of intracellular signalling pathways led to the synthesis and discovery of many agents targeting cancer cells. In this study, we investigated for the first time the effect of anticancer agent ukrain as a single agent or in combination with cisplatin, etoposide, 5-fluorouracil, quercetin and bortezomib in 4T1 breast cancer and B16F10 melanoma cells. It was found that ukrain is cytotoxic and apoptotic in 4T1 breast carcinoma and B16F10 melanoma cells when given alone. The IC50 value of ukrain in 4T1 cells was found as 40 ± 6.8 μM and that in B16F10 cells as 76 ± 10 μM. It was then found that apoptosis can be induced in 4T1 breast cancer cells in a dose-dependent manner in response to ukrain treatment, based on DNA fragmentation evidence. The induction of apoptosis was corroborated by the analysis of cleavage products of caspase-3 in 4T1 cells using Western blot technique. When ukrain was tested in combination with cisplatin and etoposide, no significant enhancement of cytotoxicity was detected as compared with single agent treatments. Similarly, 5-fluorouracil and quercetin also did not potentiate the cytotoxic effects of ukrain in 4T1 cells. Finally, we examined the effect of various concentrations of ukrain in combination with 10 nM bortezomib in 4T1 cells. Determination of combination index values showed that bortezomib potentiated the effect of ukrain. And the combination was found to cause synergistic cell death. The lowest combination index detected was 0.57 which was obtained when the cells were treated with 10 nM bortezomib + 100 μM ukrain. Likewise, when cells were treated with different doses of bortezomib in the presence of 25 μM ukrain, synergism was similarly detected between the two drugs in a dose-dependent manner. Altogether, the results presented here suggest that the combination of ukrain + bortezomib may be further evaluated and tested in clinical settings. Keywords: Apoptosis, bortezomib, cancer, synergism, ukrain.
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