Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A synthetic amphiphilic block copolymer, Pluronic, is a potent chemosensitizer of multidrug resistant (MDR) cancers that has shown promise in clinical trials. It has unique activities in MDR cells, which include a decrease in ATP pools and inhibition of P-glycoprotein (Pgp) resulting in increased drug accumulation in cells. This work demonstrates that Pluronic rapidly (15min) translocates into MDR cells and co-localizes with the mitochondria. It inhibits complex I and complex IV of the mitochondria respiratory chain, decreases oxygen consumption and causes ATP depletion in MDR cells. These effects are selective and pronounced for MDR cells compared to non-MDR counterparts and demonstrated for both drug-selected and Pgp-transfected cell models. Furthermore, inhibition of Pgp functional activity also abolishes the effects of Pluronic on intracellular ATP levels in MDR cells suggesting that Pgp contributes to increased responsiveness of molecular "targets" of Pluronic in the mitochondria of MDR cells. The Pluronic-caused impairment of respiration in mitochondria of MDR cells is accompanied with a decrease in mitochondria membrane potential, production of ROS, and release of cytochrome c. Altogether these effects eventually enhance drug-induced apoptosis and contribute to potent chemosensitization of MDR tumors by Pluronic.
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PMID:Differential metabolic responses to pluronic in MDR and non-MDR cells: a novel pathway for chemosensitization of drug resistant cancers. 1981 37

Standard chemotherapeutic protocols, based on maximum tolerated doses, do not prevent nor overcome chemoresistance caused by the efflux transporter P-glycoprotein (Pgp). We compared the effects of two consecutive low doses versus a single high dose of doxorubicin in drug-sensitive Pgp-negative and drug-resistant Pgp-positive human and murine cancer cells. Two consecutive low doses were significantly more cytotoxic in vitro and in vivo against drug-resistant tumors, while a single high dose failed to do so. The greater efficacy of two consecutive low doses of doxorubicin could be linked to increased levels of intracellular reactive oxygen species. These levels were produced by high electron flux from complex I to complex III of the mitochondrial respiratory chain, unrelated to the synthesis of ATP. This process induced mitochondrial oxidative damage, loss of mitochondrial potential and activation of the cytochrome c/caspase 9/caspase 3 pro-apoptotic axis in drug-resistant cells. Our work shows that the "apparent" ineffectiveness of doxorubicin against drug-resistant tumors overexpressing Pgp can be overcome by changing the timing of its administration and its doses.
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PMID:Two repeated low doses of doxorubicin are more effective than a single high dose against tumors overexpressing P-glycoprotein. 2568 70