Lemeshko Victor V, Kugler Wilfried
Escuela de Física, Facultad de Ciencias, Universidad Nacional de Colombia, Sede Medellín, AA3840, Medellín, Colombia.
J Biol Chem. 2007 Dec 28;282(52):37303-7. doi: 10.1074/jbc.C700134200. Epub 2007 Nov 9.
Alkylphosphocholines are a new class of anticancer agents. The mechanisms by which these drugs display their antitumor activities are not known. In this work, we show that erucylphosphohomocholine, a new antineoplastic compound, significantly decreased ATP synthesis in isolated rat liver mitochondria at a concentration of 50 microm or higher via permeabilization of the inner membrane. At a concentration of 25 microm, it induced a moderate swelling of mitochondria, a slight decrease of the inner membrane potential, and an increase in state 4 respiration without an essential influence on state 3 respiration or the outer membrane permeability to cytochrome c. We found that cyclosporin A did not prevent mitochondrial swelling induced by 25-100 microm erucylphosphohomocholine. Moreover, cyclosporin A induced a fast drop of the inner membrane potential in the presence of 25-50 microm erucylphosphohomocholine that seems to be due to a strong synergistic inhibition of the respiratory activity. The ratio of uncoupled to state 3 respiration rates increased from 1.3 +/- 0.1 with 25 microm erucylphosphohomocholine and from 1.5 +/- 0.1 with 1 microm cyclosporin A to 4.5 +/- 0.3 in the presence of both drugs. On the other hand, oligomycin or cyclosporin A protected certain cancer cell lines against erucylphosphohomocholine-induced apoptosis. This protection might be related to a prevention of cellular ATP hydrolysis by permeabilized mitochondria and to the inhibition of the classical permeability transition pore, respectively. Our findings provide new insight into the mechanisms by which these unusual alterations of mitochondria might be involved in anticancer activity of alkylphosphocholines.
烷基磷胆碱是一类新型抗癌药物。这些药物发挥抗肿瘤活性的机制尚不清楚。在这项研究中，我们发现新型抗肿瘤化合物芥酰磷高胆碱在浓度为50微摩尔或更高时，通过使线粒体内膜通透性增加，显著降低了分离的大鼠肝线粒体中的ATP合成。在浓度为25微摩尔时，它诱导线粒体适度肿胀，内膜电位略有下降，状态4呼吸增加，而对状态3呼吸或外膜对细胞色素c的通透性没有实质性影响。我们发现环孢素A不能阻止25 - 100微摩尔芥酰磷高胆碱诱导的线粒体肿胀。此外，在存在25 - 50微摩尔芥酰磷高胆碱的情况下，环孢素A会导致内膜电位快速下降，这似乎是由于对呼吸活性的强烈协同抑制作用。在两种药物共同存在时，解偶联与状态3呼吸速率的比值从25微摩尔芥酰磷高胆碱时的1.3±0.1以及1微摩尔环孢素A时的1.5±0.1增加到4.5±0.3。另一方面，寡霉素或环孢素A可保护某些癌细胞系免受芥酰磷高胆碱诱导的凋亡。这种保护作用可能分别与阻止通透化线粒体引起的细胞ATP水解以及抑制经典的通透性转换孔有关。我们的研究结果为这些线粒体异常变化可能参与烷基磷胆碱抗癌活性的机制提供了新的见解。
