BCL-2 antisense and cisplatin combination treatment of MCF-7 breast cancer cells with or without functional p53

Abstract

Chemotherapy has been used for treatment of breast cancer but with limited success. We characterized the effects of bcl-2 antisense and cisplatin combination therapy in two human isogenic breast carcinoma cells p53(+)MCF-7 and p53(-)MCF-7/E6. The transferrin-facilitated lipofection strategy we have developed yielded same transfection efficiency in both cells. Bcl-2 antisense delivered with this strategy significantly induced more cell death, apoptosis, and cytochrome c release in MCF-7/E6 than in MCF-7, but did not affect Fas level in both cells and activated caspase-8 equally. Cisplatin exerted same effects on cell viability and apoptosis in both cells, but released smaller amounts of cytochrome c while activated more caspase-8 in MCF-7/E6. The combination treatment yielded greater effects on cell viability, apoptosis, cytochrome c release, and caspase-8 activation than individual treatments in both cells although p53(-) cells were more sensitive. The potentiated activation of caspase-8 in the combination treatment suggested that caspase-8-mediated (but cytochrome c-independent) apoptotic pathway is the major contributor of the enhanced cell killing. Thus, bcl-2 antisense delivered with transferrin-facilitated lipofection can achieve the efficacy of killing breast cancer cells and sensitizing them to chemotherapy. Bcl-2 antisense and cisplatin combination treatment is a potentially useful therapeutic strategy for breast cancer irrespective of p53 status.

Combination Silencer RNA (siRNA) Targeting Bcl-2 Antagonizes siRNA against Thymidylate Synthase in Human Tumor Cell Lines

“…1-4). The degree of siRNA-mediated reduction was consistent with other reports where antisense reagents of several types were used to target Bcl-2 (Chawla- Sarkar et al, 2004;Lima et al, 2004;Basma et al, 2005;Ocker et al, 2005) or TS (Ferguson et al, 1999;Schmitz et al, 2004) protein in several human tumor cell lines.…”

αVβ3 Integrin-Targeted PLGA-PEG Nanoparticles for Enhanced Anti-tumor Efficacy of a Pt(IV) Prodrug

“…Reported values using slightly different MTT protocols are ~1.0 µM for PC3, ~1.7 µM for DU145, 46 and ~5 µM for MCF7. 47 The Pt(IV) compound, Pt(hex) 2 , was more cytotoxic in all cell lines tested compared to the Pt(II) parental compound, cisplatin. As recently reported, the high lipophilicity of a Pt(IV) complex contributes to its increased cell killing ability.…”

Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

“…CDDP exerted increased apoptosis with release of cytochrome c while activating more caspase-8. However, combinatorial treatment showed improved effects on cell viability, apoptosis, cytochrome c release, and caspase-8 activation compared to individual treatments [64]. …”