Differential metabolic responses to pluronic in MDR and non-MDR cells: A novel pathway for chemosensitization of drug resistant cancers

Abstract

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 (15 min) 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 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.

A one-step electrospray-based technique for modulating morphology and surface properties of poly(lactide-co-glycolide) microparticles using Pluronics®

“…25,26 Additionally, Pluronics ® are known to act as biological response modifiers that can be advantageous in drug delivery applications and are available in varying hydrophiliclipophilic balances (HLB) as a consequence of variation in lengths of EO and PO chains. [27][28][29] Hence, in this report, blending of hydrophobic PLGA 85:15 with a versatile class of polymer-Pluronic ® was used as the strategy for surface modification of electrosprayed PLGA microparticles. …”

The exposure of cancer cells to hyperthermia, iron oxide nanoparticles, and mitomycin C influences membrane multidrug resistance protein expression levels

“…23 Moreover, ROS-linked mechanisms have been associated with the MDR transporter p-glycoprotein. 20,[23][24][25][26][27][28][29][30][31] Low reactive oxygen species (ROS) levels upregulate, 20,24 whereas high levels downregulate 23,25,27-31 p-glycoprotein expression. Since an oxidative responsive element has also been detected in the proximity of its promoter, MRP 1 protein has also been associated with redox mechanisms.…”

Non-invasive topical drug delivery to spinal cord with carboxyl-modified trifunctional copolymer of ethylene oxide and propylene oxide

“…The observed selectivity suggests 'intracellular mode' of cytotoxicity of amphiphilic copolymers as cancer cells have more intense metabolism and higher proliferative potential, and therefore more readily accumulate copolymers in their interior [19,22]. Inside cells EO/PO copolymers were shown to interact with subcellular structures, including mitochondria, impairing some metabolic processes [28].…”