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Molecular targeting of BCL2 and BCLXL proteins by synthetic BCL2 homology 3 domain peptide enhances the efficacy of chemotherapy.
J Pharmacol Exp Ther. 2006 Mar; 316(3):992-8.JP

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16291730

Citation

Dharap, Sonia S., et al. "Molecular Targeting of BCL2 and BCLXL Proteins By Synthetic BCL2 Homology 3 Domain Peptide Enhances the Efficacy of Chemotherapy." The Journal of Pharmacology and Experimental Therapeutics, vol. 316, no. 3, 2006, pp. 992-8.
Dharap SS, Chandna P, Wang Y, et al. Molecular targeting of BCL2 and BCLXL proteins by synthetic BCL2 homology 3 domain peptide enhances the efficacy of chemotherapy. J Pharmacol Exp Ther. 2006;316(3):992-8.
Dharap, S. S., Chandna, P., Wang, Y., Khandare, J. J., Qiu, B., Stein, S., & Minko, T. (2006). Molecular targeting of BCL2 and BCLXL proteins by synthetic BCL2 homology 3 domain peptide enhances the efficacy of chemotherapy. The Journal of Pharmacology and Experimental Therapeutics, 316(3), 992-8.
Dharap SS, et al. Molecular Targeting of BCL2 and BCLXL Proteins By Synthetic BCL2 Homology 3 Domain Peptide Enhances the Efficacy of Chemotherapy. J Pharmacol Exp Ther. 2006;316(3):992-8. PubMed PMID: 16291730.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular targeting of BCL2 and BCLXL proteins by synthetic BCL2 homology 3 domain peptide enhances the efficacy of chemotherapy. AU - Dharap,Sonia S, AU - Chandna,Pooja, AU - Wang,Yang, AU - Khandare,Jayant J, AU - Qiu,Bo, AU - Stein,Stanley, AU - Minko,Tamara, Y1 - 2005/11/15/ PY - 2005/11/18/pubmed PY - 2006/4/14/medline PY - 2005/11/18/entrez SP - 992 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 316 IS - 3 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16291730/Molecular_targeting_of_BCL2_and_BCLXL_proteins_by_synthetic_BCL2_homology_3_domain_peptide_enhances_the_efficacy_of_chemotherapy_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16291730 DB - PRIME DP - Unbound Medicine ER -