Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs

Tanabe, Kazuaki; Kim, Ryungsa; Inoue, Hideki; Emi, Manabu; Uchida, Yuzo; Toge, Tetsuya

doi:10.3892/ijo.22.4.875

Cited by 26 publications

(34 citation statements)

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“…Several studies have shown that a reduction in Bcl-2 levels increased the sensitivity to paclitaxel in breast cancer (40,41) and multiple myeloma cells (42). The dependence of Bim-induced apoptosis on Bax and Bad, coupled with the role of Bcl-2 in paclitaxel-induced apoptosis would support our assertion that Bim does have a role in modulating the apoptotic response to taxanes.…”

Section: Discussionsupporting

confidence: 71%

FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines

Sunters

Mattos

Ståhl

et al. 2003

Journal of Biological Chemistry

461

389

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Paclitaxel is used to treat breast cancers, but the mechanisms by which it induces apoptosis are poorly understood. Consequently, we have studied the role of the FoxO transcription factors in determining cellular response to paclitaxel. Western blotting revealed that in a panel of nine breast cancer cell lines expression of FoxO1a and FoxO3a correlated with the expression of the pro-apoptotic FoxO target Bim, which was associated with paclitaxel-induced apoptosis. In MCF-7 cells, which were paclitaxel-sensitive, the already high basal levels of FoxO3a and Bim protein increased dramatically after drug treatment, as did Bim mRNA, which correlated with apoptosis induction. This was not observed in MDA-231 cells, which expressed low levels of FoxOs and Bim. Gene reporter experiments demonstrated that in MCF-7 cells maximal induction of Bim promoter was dependent on a FoxO binding site, suggesting that FoxO3a is responsible for the transcriptional up-regulation of Bim. Gene silencing experiments showed that small interference RNA (siRNA) specific for FoxO3a reduced the levels of FoxO3a and Bim protein as well as inhibited apoptosis in paclitaxel-treated MCF-7 cells. Furthermore, siRNA specific for Bim reduced the levels of Bim protein and inhibited apoptosis in paclitaxel-treated MCF-7 cells. This is the first demonstration that up-regulation of FoxO3a by paclitaxel can result in increased levels of Bim mRNA and protein, which can be a direct cause of apoptosis in breast cancer cells.Breast cancer is one of the most common malignancies affecting women in the western world and arises following the accumulation of a series of somatic changes that serve to increase the rate of cellular proliferation and/or reduce the levels of apoptosis. These changes are often found to involve deregulation of key signal transduction pathways. Signal transduction pathways within the cell transmit the extracellular signals to transcription factors, resulting in changes in gene expression. These changes in gene expression are often cell typespecific and lead to cell growth, differentiation, or apoptosis, thereby regulating normal tissue structure and function. One key signal transduction pathway highly conserved in eukaryotes is the phosphatidylinositol 3-kinase (PI3K) 1 pathway (1), which is stimulated by a number of growth factors, including insulin and insulin-like growth factor 1 (1). Once a receptor tyrosine kinase has become activated by binding a specific ligand, it becomes autophosphorylated and binds PI3K heterodimers either directly, or indirectly via insulin receptor substrate (IRS) adaptor proteins (1-3). The interaction between the p85 regulatory subunit of PI3K and the receptor brings the catalytic domain (p110 subunit) of PI3K into contact with the plasma membrane, where it is able to phosphorylate its targets. Alternatively, PI3K can be juxtaposed to the plasma membrane via interactions with activated RAS family members. PI3K phosphorylates phosphatidylinositol (4,5)-diphosphate at the 3 position, resulting in the formatio...

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Section: Discussionsupporting

confidence: 71%

FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines

Sunters

Mattos

Ståhl

et al. 2003

Journal of Biological Chemistry

461

389

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“…These studies provide evidence that a combination of ASOs against both proliferation and prosurvival associated targets may represent a promising antitumoral therapeutic approach. Moreover, the simultaneous suppression of different pathways significantly enhances the cytotoxicity of conventional antitumoral drugs; therefore it can be used in the treatment of resistant tumors (Liu and Gazitt, 2003;Pakunlu et al, 2003;Tanabe et al, 2003). Recent findings obtained by independent research groups, including ours, demonstrate that Bcl-2 is also involved in the angiogenesis process through a mechanism that, at least in part, appears to be independent of its antiapoptotic function (Biroccio et al, 2000;Fernandez et al, 2001, Iervolino et al, 2002.…”

Section: Bcl-2 Familymentioning

confidence: 99%

The future of antisense therapy: combination with anticancer treatments

Biroccio¹,

Leonetti²,

Zupi³

2003

Oncogene

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“…This concept has been proved valid through anti-sense approach. [5][6][7] Anti-apoptotic Bcl-2 proteins are a subgroup of the Bcl-2 protein family, including Bcl-2, Bcl-X L , Bcl-w, Mcl-1, and A1. In some cancers, more than one anti-apoptotic Bcl-2 protein is coover-expressed.…”

Section: Introductionmentioning

confidence: 99%

Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1

Xing

Wang

Tang

et al. 2007

Bioorganic & Medicinal Chemistry

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A series of inhibitors for anti-apoptotic Bcl-2 proteins based on BHI-1 were synthesized and their binding interactions with Bcl-2, Bcl-X L , and Bcl-w were evaluated. It was found that modification of BHI-1 resulted in varied binding profiles among Bcl-2, Bcl-X L , and Bcl-w and a set of inhibitors with varied selectivity to Bcl-2, Bcl-X L , and Bcl-w protein have been identified. Molecular modeling of the interaction of the BHI-1 based analogs with the anti-apoptotic Bcl-2 proteins suggested that the binding site for the BHI-1 based inhibitor was the least conserved section among Bcl-2, Bcl-X L , and Bcl-w: targeting the non-conserved section may account for the observed selectivity of the BHI-1 based inhibitors among the anti-apoptotic Bcl-2 proteins. The validity of the model was supported by a strong correlation between the model-calculated binding energy and the experimental binding affinity. In summary, our studies suggest that most of the reported inhibitors for antiapoptotic Bcl-2 proteins are nonselective and BHI-1 is a promising template to distinguish among Bcl-2, Bcl-X L , and Bcl-w by targeting the nonconserved domain among the anti-apoptotic Bcl-2 proteins. Molecular-modeling aided rational development of BHI-1 based selective inhibitor for antiapoptotic Bcl-2 proteins is underway.

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Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs

Cited by 26 publications

References 0 publications

FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines

FoxO3a Transcriptional Regulation of Bim Controls Apoptosis in Paclitaxel-treated Breast Cancer Cell Lines

The future of antisense therapy: combination with anticancer treatments

Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1

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