Fedotcheva Tatiana A, Kruglov Alexey G, Fedotcheva Nadezhda I
Science Research Laboratory of Molecular Pharmacology, Medical Biological Faculty, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, 1, Ostrovityanova st., Moscow 117997, Russia.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 3, Institutskaya st., Pushchino 142290, Russia.
Pharmaceuticals (Basel). 2025 Jun 19;18(6):924. doi: 10.3390/ph18060924.
: Tariquidar (Tq) is an inhibitor of the multidrug resistance (MDR) proteins relevant to ATP-binding cassette transporters (ABC transporters), which suppresses the ATP-dependent efflux of a variety of hydrophilic and amphipathic compounds, including anticancer drugs. Tq is a representative of a new generation of MDR inhibitors with high affinity to ABC proteins. However, there are still no data on the possible effect of Tq on mitochondria as an important target in the regulation of cell death or survival. : We investigated the influence of Tq on the Ca-dependent mitochondrial permeability transition pore (mPTP). The effect of Tq was assessed using several parameters, including the calcium load, membrane potential, and mitochondrial swelling. To evaluate the specific targets of Tq, selective inhibitors of components of the mitochondrial pore were used, including adenine nucleotides, carboxyatractylozide (Catr) and bongkrekic acid (BA), oligomycin, and cyclosporine A. : Tq decreased the calcium retention capacity, activated mitochondrial swelling, and lowered the influence of ADP and ATP, the inhibitors of the Ca-induced pore opening, at their low concentrations. These effects of Tq were observed in both calcium-load and swelling assays, thus mimicking the effect of Catr, a selective inhibitor of adenine nucleotide translocase (ANT). Tq also decreased the protective effect of BA, an inhibitor of ANT and mPTP, on the calcium retention capacity of mitochondria. Further, Tq dose-dependently decreased the inhibitory effect of a low ATP concentration but not of high concentrations, at which the effect of Tq was activated by oligomycin, an inhibitor of F-ATP synthase. : The influence of Tq extends to mitochondria, specifically to the regulation of membrane permeability, promoting the activation of pore opening, probably through an interaction with ANT, a component of the pore-forming complex. The effect of Tq on the opening of mPTP is strongly dependent on the concentrations of adenine nucleotides and, consequently, on the functional state of mitochondria. The direct influence of Tq on mitochondria can be considered as a new activity that promotes the sensitization of cells to various treatments and stimuli.
塔里喹达（Tq）是一种与ATP结合盒转运蛋白（ABC转运蛋白）相关的多药耐药（MDR）蛋白抑制剂，它能抑制包括抗癌药物在内的多种亲水性和两亲性化合物的ATP依赖性外排。Tq是新一代对ABC蛋白具有高亲和力的MDR抑制剂的代表。然而，关于Tq对作为细胞死亡或存活调节重要靶点的线粒体可能产生的影响，目前仍没有相关数据。
我们研究了Tq对钙依赖性线粒体通透性转换孔（mPTP）的影响。使用了包括钙负荷、膜电位和线粒体肿胀等多个参数来评估Tq的作用。为了评估Tq的特定靶点，使用了线粒体孔成分的选择性抑制剂，包括腺嘌呤核苷酸、羧基苍术苷（Catr）和硼酸（BA）、寡霉素和环孢素A。
Tq降低了钙保留能力，激活了线粒体肿胀，并在低浓度时降低了ADP和ATP（钙诱导孔开放的抑制剂）的影响。在钙负荷和肿胀试验中均观察到Tq的这些作用，从而模拟了腺嘌呤核苷酸转位酶（ANT）的选择性抑制剂Catr的作用。Tq还降低了ANT和mPTP的抑制剂BA对线粒体钙保留能力的保护作用。此外，Tq剂量依赖性地降低了低ATP浓度的抑制作用，但对高浓度没有影响，在高浓度时Tq的作用被F-ATP合酶抑制剂寡霉素激活。
Tq的影响延伸到线粒体，特别是对膜通透性的调节，可能通过与成孔复合物的成分ANT相互作用促进孔开放的激活。Tq对mPTP开放的影响强烈依赖于腺嘌呤核苷酸的浓度，因此也依赖于线粒体的功能状态。Tq对线粒体的直接影响可被视为一种新的活性，它促进细胞对各种治疗和刺激的敏感性。
