Differential metabolic responses to pluronic in MDR and non-MDR cells: a novel pathway for chemosensitization of drug resistant cancers.
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.
Alakhova
Daria Yu
DY
Center for Drug Delivery and Nanomedicine and Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-5830, United States.
Rapoport
Nataliya Y
NY
Batrakova
Elena V
EV
Timoshin
Alexander A
AA
Li
Shu
S
Nicholls
David
D
Alakhov
Valery Yu
VY
Kabanov
Alexander V
AV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy*; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D020442:Poloxamer / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D020442:Poloxamer; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C039900:nitroxyl