Department of Chemistry and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22199-204. doi: 10.1073/pnas.0912276106. Epub 2009 Dec 10.
The unique glycolytic metabolism of most solid tumors, known as the Warburg effect, is associated with resistance to apoptosis that enables cancer cells to survive. Dichloroacetate (DCA) is an anticancer agent that can reverse the Warburg effect by inhibiting a key enzyme in cancer cells, pyruvate dehydrogenase kinase (PDK), that is required for the process. DCA is currently not approved for cancer treatment in the USA. Here, we present the synthesis, characterization, and anticancer properties of c,t,c-[Pt(NH(3))(2)(O(2)CHCl(2))(2)Cl(2)], mitaplatin, in which two DCA units are appended to the axial positions of a six-coordinate Pt(IV) center. The negative intracellular redox potential reduces the platinum to release cisplatin, a Pt(II) compound, and two equivalents of DCA. By a unique mechanism, mitaplatin thereby attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. The cytotoxicity of mitaplatin in a variety of cancer cell lines equals or exceeds that of all known Pt(IV) compounds and is comparable to that of cisplatin. Mitaplatin alters the mitochondrial membrane potential gradient (Deltapsi(m)) of cancer cells, promoting apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from mitochondria to the nucleus. Cisplatin formed upon cellular reduction of mitaplatin enters the nucleus and targets DNA to form 1,2-intrastrand d(GpG) cross-links characteristic of its own potency as an anticancer drug. These properties of mitaplatin are manifest in its ability to selectively kill cancer cells cocultured with normal fibroblasts and to partially overcome cisplatin resistance.
大多数实体瘤独特的糖酵解代谢，即沃伯格效应，与抗细胞凋亡有关，使癌细胞能够存活。二氯乙酸（DCA）是一种抗癌药物，可通过抑制癌细胞中丙酮酸脱氢酶激酶（PDK）来逆转沃伯格效应，该酶是该过程所必需的。DCA 目前未被批准用于美国的癌症治疗。在这里，我们提出了 c，t，c-[Pt（NH 3 ）（2）（O 2 CHCl 2 ）（2）Cl 2 ]，米他铂的合成、表征和抗癌特性，其中两个 DCA 单元附加到六配位 Pt（IV）中心的轴向位置。负细胞内氧化还原电势将铂还原为释放顺铂，一种 Pt（II）化合物和两个当量的 DCA。通过独特的机制，米他铂因此攻击核 DNA 与顺铂和线粒体与 DCA 选择性在癌细胞中。米他铂在各种癌细胞系中的细胞毒性等于或超过所有已知的 Pt（IV）化合物，并且与顺铂相当。米他铂改变癌细胞的线粒体膜电位梯度（Deltapsi（m）），通过释放细胞色素 c 和将凋亡诱导因子从线粒体转移到细胞核来促进凋亡。米他铂还原后形成的顺铂进入细胞核并靶向 DNA 形成其作为抗癌药物自身效力的特征性 1,2-链内 d（GpG）交联。米他铂的这些特性表现为其选择性杀死与正常成纤维细胞共培养的癌细胞的能力，并部分克服顺铂耐药性。
