Bcl-2/bcl-xL Bispecific Antisense Treatment Sensitizes Breast Carcinoma Cells to Doxorubicin, Paclitaxel and Cyclophosphamide

Abstract

Overexpression of the anti-apoptotic proteins bcl-2 and bcl-xL is implicated in breast cancer development, tumor progression and drug resistance. Here we describe the use of the bcl-2/bcl-xL bispecific antisense oligonucleotide 4625 to sensitize breast carcinoma cells to anti-cancer drugs routinely used in breast cancer therapy. MCF7 cells were treated with oligonucleotide 4625, doxorubicin, paclitaxel or cyclophosphamide alone, or with combinations of oligonucleotide and the anti-cancer drugs. As measured in cell viability assays, treatment with the various combinations reduced the number of viable MCF7 cells more effectively than treatment with the single drugs alone. Treatment with a sequence control oligonucleotide did not affect cell viability. All combination treatments induced apoptosis as demonstrated by the appearance of massive nuclear condensation in a high proportion of the cells. To further characterize the interaction between 4625 and doxorubicin, paclitaxel or cyclophosphamide, the median-effect method was used. In MCF7 cells all combinations resulted in potent synergistic effects over a broad range of toxicity with combination indices ranging from 0.8 to 0.1. Similarly, strong synergistic interactions between oligonucleotide 4625 and the anti-cancer drugs were also observed in cultures of the breast carcinoma cell line MDA-MB-231. Our data suggest the use of 4625 as a potent adjuvant in breast cancer chemotherapy.

p38 MAPK downregulates phosphorylation of Bad in doxorubicin-induced endothelial apoptosis

“…Lorenzo and coworkers [35] have reported that doxorubicin-induced apoptosis includes a downregulation of Bcl-2 protein and involvement of the mitochondrial pathway. Overexpression of Bcl-xL has been observed to protect cardiomyocytes from doxorubicin-provoked apoptosis [50,51], and bcl-2/bcl-xL bispecific antisense treatment has been found to sensitize breast carcinoma cells to doxorubicin [52], suggesting an important survival function for Bcl-2 and/or Bcl-xL in cells exposed to doxorubicin.…”

Gene expression profilers and conventional clinical markers to predict distant recurrences for premenopausal breast cancer patients after adjuvant chemotherapy

“…tumor size) may correlate more directly to the progression of the disease. The huge amount of information embedded in genome-wide studies should, in principle, allow for extraction of both kind of markers in gene expression data, but it is not inconceivable that genome-wide profiling is more related to disease subtypes (16,42) than to progression. If so, gene expression analysis may be better suited for studies aiming at an improved biological insight to the mechanisms behind the studied disease and its subtypes, potentially leading to the discovery of new drug targets and development of new therapeutic protocols.…”

“…To find the reporters on our array corresponding to the genes on our pre-defined gene lists, we used the official gene symbol. The gene symbols for the van 't Veer gene list (16) were obtained through ACID (39) using UniGene build 176, and the official gene symbols for the drug-genes were found manually using Gene and Locus Link. All reporters on our array that according to UniGene build 180 had a gene symbol represented on the resulting list were selected.…”

“…Studies using these techniques in breast cancer have shown distinct differences in gene expression profile between hereditary and sporadic breast cancer (15), and between ER positive and ER negative cancer (16,17). Promising results have also been obtained for predicting clinical outcome (17-21), both in patients not treated with adjuvant therapy (19)(20)(21) and in patients treated with adjuvant therapy, endocrine, chemotherapy, or both (17)(18)(19).…”

Retrovirus-mediated tk gene therapy of implanted human breast cancer in nude mice under the regulation of Tet-On

“…Breast cancer gene therapy has generally been considered to be tumorostatic, thus implying that the predominant mechanism is involved in the induction of cell death or apoptosis. 28,29 Recently, however, there have been several studies showing that breast cancer is to some extent a cell cycle disease. 30,31 The cell cycle coordination takes place mainly at G 1 /S and G 2 /M phase transitions by a series of checkpoints.…”