Pluronic block copolymers alter apoptotic signal transduction of doxorubicin in drug-resistant cancer cells

• Published in: Journal of controlled release Vol. 105; no. 3; pp. 269 - 278
• Main Authors: Minko, Tamara, Batrakova, Elena V., Li, Shu, Li, Yili, Pakunlu, Refika I., Alakhov, Valery Yu, Kabanov, Alexander V.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 20.07.2005; Elsevier
• Subjects: Annexin A5 - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Breast Neoplasms - metabolism; Cell Line, Tumor; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Enzyme Inhibitors - pharmacology; Epithelial Cells - metabolism; Excipients - pharmacology; Female; Gene Expression Regulation - drug effects; General pharmacology; Genes, MDR; Humans; In Situ Nick-End Labeling; KB Cells; Medical sciences; Microscopy, Confocal; Microscopy, Fluorescence; Multidrug resistance; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Pluronic; Poloxamer - pharmacology; Polymer; Signal Transduction - drug effects; Solutions; Polymer; Pluronic; Multidrug resistance; Apoptosis; Antineoplastic agent; Drug; DNA topoisomerase (ATP-hydrolysing); Pharmaceutical technology; Enzyme; Control release polymer; Vehicle(excipient); Enzyme inhibitor; Laxative; Doxorubicin; Signal transduction; Antibiotic; Isomerases; Cell death; Multiple resistance; Poloxamer; Anthracyclins; Tumor cell; Block copolymer
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2005.03.019

Pluronic block copolymer P85 (P85) sensitizes multidrug resistant (MDR) cancer cells resulting in the increase of cytotoxic activity of antineoplastic agents. This effect is attributed to the inhibition of the most clinically relevant drug efflux transporter, P-glycoprotein (Pgp), through the combined ATP depletion and inhibition of Pgp ATPase activity. The present study elucidates effects of an anticancer agent, doxorubicin (Dox), formulated with P85 on drug-induced apoptosis in MDR cancer cells. Early and late stages of apoptosis were detected by Annexin V and TUNEL methods, respectively. In parallel experiments, the expression of genes related to apoptosis, BCL2, BCLXL, BAX, P53, APAF1, Caspase 3, and Caspase 9, was determined by RT-PCR. The obtained data suggest that Dox/P85 formulation induces apoptosis in the resistant cancer cells more efficiently than free Dox. The treatment of the cells with Dox alone simultaneously activated a proapoptotic signal and an antiapoptotic cellular defense. Therefore, the apoptosis induction by Dox was substantially limited. In contrast, the treatment of the cells with Dox/P85 formulation significantly enhanced the proapoptotic activity of the drug and prevented the activation of the antiapoptotic cellular defense. This is likely to result in the stronger cytotoxic response of the resistant cells to the Dox/P85 formulation compared to the free drug.