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.
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: S Motomura; T Motoji; M Takanashi; Y H Wang; H Shiozaki; I Sugawara; E Aikawa; A Tomida; T Tsuruo; N Kanda; H Mizoguchi Journal: Blood Date: 1998-05-01 Impact factor: 22.113
Authors: Olga B Garbuzenko; Maha Saad; Vitaly P Pozharov; Kenneth R Reuhl; Gediminas Mainelis; Tamara Minko Journal: Proc Natl Acad Sci U S A Date: 2010-05-24 Impact factor: 11.205
Authors: Alex M Chen; Min Zhang; Dongguang Wei; Dirk Stueber; Oleh Taratula; Tamara Minko; Huixin He Journal: Small Date: 2009-12 Impact factor: 13.281
Authors: Hyunmin Kang; Michael H Fisher; Dong Xu; Yuko J Miyamoto; Arnaud Marchand; Arthur Van Aerschot; Piet Herdewijn; Rudolph L Juliano Journal: Nucleic Acids Res Date: 2004-08-17 Impact factor: 16.971