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Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin.
Pharm Res. 2003 Mar; 20(3):351-9.PR

Abstract

PURPOSE

To enhance the anticancer efficacy of an established drug by the simultaneous suppression of pump and nonpump cellular resistance.

METHODS

Multidrug resistant human ovarian (A2780/AD) and breast (MCF-7/AD) cancer cells were used. Doxorubicin (DOX) and antisense oligonucleotides (ASO) targeted to MDR1 and BCL-2 mRNA were combined in a solution within one liposomal drug delivery system (LDDS) in different combination series. Ten series of experiments were performed. In each series cells were incubated with 12 to 45 concentrations of free DOX and different liposomal formulations over a period of 6 to 48 h. Cytotoxicity, apoptosis induction, caspases, MDR1., BCL-2, and APAF-1 genes, P-glycoprotein, and BCL-2 protein were studied.

RESULTS

The combination of DOX and ASO targeted to MDR1 and BCL-2 mRNA in one LDDS exhibited a dramatic increase in the anticancer action of DOX. As a result of the simultaneous suppression of pump and nonpump cellular resistance by the inhibition of P-glycoprotein and BCL-2 protein synthesis, a significant increase in the activation of caspases and apoptosis was observed.

CONCLUSIONS

The simultaneous suppression of multidrug resistance and antiapoptotic cellular defense significantly enhanced the anticancer activity of DOX. Therefore, the proposed DDS combination may potentially be used in the treatment of multidrug-resistant ovarian and breast cancers.

Authors+Show Affiliations

Department of Pharmaceutics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12669953

Citation

Pakunlu, Refika I., et al. "Simultaneous Modulation of Multidrug Resistance and Antiapoptotic Cellular Defense By MDR1 and BCL-2 Targeted Antisense Oligonucleotides Enhances the Anticancer Efficacy of Doxorubicin." Pharmaceutical Research, vol. 20, no. 3, 2003, pp. 351-9.
Pakunlu RI, Cook TJ, Minko T. Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin. Pharm Res. 2003;20(3):351-9.
Pakunlu, R. I., Cook, T. J., & Minko, T. (2003). Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin. Pharmaceutical Research, 20(3), 351-9.
Pakunlu RI, Cook TJ, Minko T. Simultaneous Modulation of Multidrug Resistance and Antiapoptotic Cellular Defense By MDR1 and BCL-2 Targeted Antisense Oligonucleotides Enhances the Anticancer Efficacy of Doxorubicin. Pharm Res. 2003;20(3):351-9. PubMed PMID: 12669953.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin. AU - Pakunlu,Refika I, AU - Cook,Thomas J, AU - Minko,Tamara, PY - 2003/4/3/pubmed PY - 2004/2/27/medline PY - 2003/4/3/entrez SP - 351 EP - 9 JF - Pharmaceutical research JO - Pharm Res VL - 20 IS - 3 N2 - PURPOSE: To enhance the anticancer efficacy of an established drug by the simultaneous suppression of pump and nonpump cellular resistance. METHODS: Multidrug resistant human ovarian (A2780/AD) and breast (MCF-7/AD) cancer cells were used. Doxorubicin (DOX) and antisense oligonucleotides (ASO) targeted to MDR1 and BCL-2 mRNA were combined in a solution within one liposomal drug delivery system (LDDS) in different combination series. Ten series of experiments were performed. In each series cells were incubated with 12 to 45 concentrations of free DOX and different liposomal formulations over a period of 6 to 48 h. Cytotoxicity, apoptosis induction, caspases, MDR1., BCL-2, and APAF-1 genes, P-glycoprotein, and BCL-2 protein were studied. RESULTS: The combination of DOX and ASO targeted to MDR1 and BCL-2 mRNA in one LDDS exhibited a dramatic increase in the anticancer action of DOX. As a result of the simultaneous suppression of pump and nonpump cellular resistance by the inhibition of P-glycoprotein and BCL-2 protein synthesis, a significant increase in the activation of caspases and apoptosis was observed. CONCLUSIONS: The simultaneous suppression of multidrug resistance and antiapoptotic cellular defense significantly enhanced the anticancer activity of DOX. Therefore, the proposed DDS combination may potentially be used in the treatment of multidrug-resistant ovarian and breast cancers. SN - 0724-8741 UR - https://www.unboundmedicine.com/medline/citation/12669953/Simultaneous_modulation_of_multidrug_resistance_and_antiapoptotic_cellular_defense_by_MDR1_and_BCL_2_targeted_antisense_oligonucleotides_enhances_the_anticancer_efficacy_of_doxorubicin_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=12669953.ui DB - PRIME DP - Unbound Medicine ER -