Molecular targeting of BCL2 and BCLXL proteins by synthetic BCL2 homology 3 domain peptide enhances the efficacy of chemotherapy.
Chemotherapeutic agents are known to induce programmed cell death or apoptosis. The activation of cellular antiapoptotic defense that prevents the translation of drug-induced damage into cell death is the key factor in cellular antiapoptotic resistance that decreases the chemotherapeutic effectiveness of a broad spectrum of anticancer drugs. A novel proapoptotic anticancer drug delivery system (DDS) was designed to simultaneously induce apoptosis and suppress antiapoptotic cellular defense. The system includes three main components: 1) anticancer drug camptothecin (CPT) as an apoptosis inducer, 2) synthetic BCL2 homology 3 domain (BH3) peptide as a suppressor of cellular antiapoptotic defense, and 3) poly(ethylene glycol) (PEG) polymer as a carrier. The above DDS was studied in vitro using A2780 human ovarian carcinoma cells and in vivo on nude mice bearing xenografts of human ovarian tumor. The results obtained in both series of experiments corroborate each other. They show that the designed DDS provided intracellular delivery of active components and suppressed cellular antiapoptotic defense, leading to the more pronounced induction of caspase-dependent signaling pathway of apoptosis compared with CPT alone and simple CPT-PEG conjugate. Including BH3 peptide in complex DDS decreased apoptotic cellular defense, substantially increased toxicity of the whole complex, and provided high antitumor activity. Therefore, the proposed novel multicomponent proapoptotic anticancer drug delivery system has high potential to enhance the efficacy of chemotherapy.
Dharap
Sonia S
SS
Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.
Chandna
Pooja
P
Wang
Yang
Y
Khandare
Jayant J
JJ
Qiu
Bo
B
Stein
Stanley
S
Minko
Tamara
T
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000008:administration & dosage*; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011092:Polyethylene Glycols; D020169:Caspases; D002166:Camptothecin