An essential relationship between ATP depletion and chemosensitizing activity of Pluronic block copolymers.
Pluronic block copolymers are known to sensitize multidrug resistant (MDR) tumors with respect to various anticancer agents, particularly, anthracycline antibiotics. After completion of the Phase I clinical trial, the formulation containing doxorubicin and Pluronic, SP1049C, is undergoing Phase II clinical trials. Studies of the mechanism of the sensitization effect of Pluronic suggested an essential role of ATP depletion in MDR tumors by the block copolymer. The ATP depletion phenomenon was further examined using a panel of cells with varying levels of expression of P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs). Cell responses were characterized in terms of EC(50), a concentration of Pluronic P85 resulting in a 50% decrease in ATP intracellular levels. These studies suggested that the cells displaying high responses in ATP depletion with EC(50)<0.01% were strongly sensitized by the block copolymer resulting in drastic increases of doxorubicin cytotoxic activity (over 100-fold). In contrast, the less responsive cells with EC(50)>ca. 0.02% were practically not sensitized by the block copolymer. The responses of the cells to P85 in ATP depletion studies correlated with the levels of expression of the drug efflux transport proteins, primarily Pgp. This provided initial evidence that Pgp may be useful as a gene expression marker for predicting potential responses to doxorubicin/Pluronic formulation in chemotherapy of cancer.
Kabanov
Alexander V
AV
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198, USA. akabanov@unmc.edu
Batrakova
Elena V
EV
Alakhov
Valery Yu
VY
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D020442:Poloxamer / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D020442:Poloxamer; D000255:Adenosine Triphosphate