School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
Department of Medical Oncology, Concord Repatriation General Hospital, Concord, NSW 2137, Australia.
Int J Mol Sci. 2020 Oct 12;21(20):7500. doi: 10.3390/ijms21207500.
In the present study, cisplatin, artemisinin, and oleanolic acid were evaluated alone, and in combination, on human ovarian A2780, A2780, and A2780 cancer cell lines, with the aim of overcoming cisplatin resistance and side effects. Cytotoxicity was assessed by MTT reduction assay. Combination index (CI) values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. Moreover, 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780 cells. The proteins were found to play critical roles in cell cycle regulation, metabolism, and biosynthetic processes and drug resistance and detoxification. Results indicate that appropriately sequenced combinations of cisplatin with artemisinin (ART) and oleanolic acid (OA) may provide a means to reduce side effects and circumvent platinum resistance.
在本研究中，评估了顺铂、青蒿素和齐墩果酸单独及联合用于人卵巢 A2780、A2780 和 A2780 癌细胞系，目的是克服顺铂耐药性和副作用。通过 MTT 还原测定评估细胞毒性。组合指数 (CI) 值用于衡量联合药物效应。MALDI TOF/TOF MS/MS 和 2-DE 凝胶电泳用于鉴定卵巢癌中的蛋白质生物标志物并评估联合效应。组合的协同作用取决于浓度和给药顺序。一般来说，推注最具协同作用。此外，有 49 种蛋白质表达差异倍数≥2：CYPA、EIF5A1、Op18、p18、LDHB、P4HB、HSP7C、GRP94、ERp57、mortalin、IMMT、CLIC1、NM23、PSA3、1433Z 和 HSP90B 下调，而 hnRNPA1、hnRNPA2/B1、EF2、GOT1、EF1A1、VIME、BIP、ATP5H、APG2、VINC、KPYM、RAN、PSA7、TPI、PGK1、ACTG 和 VDAC1 上调，而 TCPA、TCPH、TCPB、PRDX6、EF1G、ATPA、ENOA、PRDX1、MCM7、GBLP、PSAT、Hop、EFTU、PGAM1、SERA 和 CAH2 在 A2780 细胞中未表达。这些蛋白质被发现在细胞周期调控、代谢和生物合成过程以及耐药性和解毒中发挥关键作用。结果表明，顺铂与青蒿素 (ART) 和齐墩果酸 (OA) 适当排序的组合可能提供一种减少副作用和规避铂耐药性的方法。
