Zajac Juraj, Kostrhunova Hana, Novohradsky Vojtech, Vrana Oldrich, Raveendran Raji, Gibson Dan, Kasparkova Jana, Brabec Viktor
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic; Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, CZ-61265 Brno, Czech Republic.
J Inorg Biochem. 2016 Mar;156:89-97. doi: 10.1016/j.jinorgbio.2015.12.003. Epub 2015 Dec 31.
The molecular and cellular mechanisms of enhanced toxic effects in tumor cells of the Pt(IV) derivatives of antitumor oxaliplatin containing axial dichloroacetate (DCA) ligands were investigated. DCA ligands were chosen because DCA has shown great potential as an apoptosis sensitizer and anticancer agent reverting the Wartburg effect. In addition, DCA reverses mitochondrial changes in a wide range of cancers, promoting tumor cell apoptosis in a mitochondrial-dependent pathway. We demonstrate that (i) the transformation of oxaliplatin to its Pt(IV) derivatives containing axial DCA ligands markedly enhances toxicity in cancer cells and helps overcome inherent and acquired resistance to cisplatin and oxaliplatin; (ii) a significant fraction of the intact molecules of DCA conjugates with Pt(IV) derivative of oxaliplatin accumulates in cancer cells where it releases free DCA; (iii) mechanism of biological action of the Pt(IV) derivatives of oxaliplatin containing DCA ligands is connected with the effects of DCA released in cancer cells from the Pt(IV) prodrugs on mitochondria and metabolism of glucose; (iv) treatments with the Pt(IV) derivatives of oxaliplatin containing DCA ligands activate an autophagic response in human colorectal cancer cells; (v) the toxic effects in cancer cells of the Pt(IV) derivatives of oxaliplatin containing DCA ligands can be potentiated if cells are treated with these prodrugs in combination with 5-fluorouracil. These properties of the Pt(IV) derivatives of oxaliplatin containing DCA ligands provide opportunities for further development of new platinum-based agents with the capability of killing cancer cells resistant to conventional antitumor platinum drugs used in the clinic.
研究了含轴向二氯乙酸（DCA）配体的抗肿瘤奥沙利铂的Pt(IV)衍生物在肿瘤细胞中增强毒性作用的分子和细胞机制。选择DCA配体是因为DCA作为一种凋亡敏化剂和逆转瓦伯格效应的抗癌剂已显示出巨大潜力。此外，DCA可逆转多种癌症中的线粒体变化，通过线粒体依赖途径促进肿瘤细胞凋亡。我们证明：（i）奥沙利铂向含轴向DCA配体的Pt(IV)衍生物的转化显著增强了癌细胞中的毒性，并有助于克服对顺铂和奥沙利铂的固有及获得性耐药性；（ii）奥沙利铂的Pt(IV)衍生物与DCA的完整分子的很大一部分在癌细胞中积累，并在其中释放游离的DCA；（iii）含DCA配体的奥沙利铂的Pt(IV)衍生物的生物作用机制与癌细胞中从Pt(IV)前药释放的DCA对线粒体和葡萄糖代谢的影响有关；（iv）用含DCA配体的奥沙利铂的Pt(IV)衍生物处理可激活人结肠癌细胞中的自噬反应；（v）如果用这些前药与5-氟尿嘧啶联合处理细胞，含DCA配体的奥沙利铂的Pt(IV)衍生物在癌细胞中的毒性作用可增强。含DCA配体的奥沙利铂的Pt(IV)衍生物的这些特性为进一步开发新型铂类药物提供了机会这些药物能够杀死对临床使用的传统抗肿瘤铂类药物耐药的癌细胞。
