Suppression of Adriamycin-induced Apoptosis by Sustained Activation of the Phosphatidylinositol-3′-OH kinase-Akt Pathway

Takeuchi, Kenji; Ito, F.

doi:10.1074/jbc.m306615200

Cited by 29 publications

(19 citation statements)

References 65 publications

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“…The relationship of cell signaling pathway and chemical drug resistance has been largely studied recently. It was widely accepted that PI3K-Akt pathway activation was correlated with invasive behavior of tumor cells and resistance to adriamycin induced apoptosis [6,24]. Our study showed inhibiting PI3K pathway can increase the sensitivity to adriamycin in HER-2/neu overexpression breast tumor cells with wildtype p53, but not in MDA-MB-453 cells with mutant p53, strongly suggesting that wild-type p53 is also required for the proapoptotic effects of down-regulation of p-Akt activity.…”

Section: Discussionsupporting

confidence: 50%

Downregulation of wild-type p53 protein by HER-2/neu mediated PI3K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy

Ren

et al. 2004

Cell Res

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Overexpression and activation of HER-2/neu (also known as c-erbB-2), a proto-oncogene, was found in about 30% of human breast cancers, promoting cancer growth and making cancer cells resistant to chemo-and radio-therapy. Wild-type p53 is crucial in regulating cell growth and apoptosis and is found to be mutated or deleted in 60-70% of human cancers. And some cancers with a wild-type p53 do not have normal p53 function, suggesting that it is implicated in a complex process regulated by many factors. In the present study, we showed that the overexpression of HER-2/neu could decrease the amount of wild-type p53 protein via activating PI3K pathway, as well as inducing MDM2 nuclear translocation in MCF7 human breast cancer cells. Blockage of PI3K pathway with its specific inhibitor LY294002 caused G1-S phase arrest, decreased cell growth rate and increased chemo-and radio-therapeutic sensitivity in MCF7 cells expressing wild-type p53. However, it did not increase the sensitivity to adriamycin in MDA-MB-453 breast cancer cells containing mutant p53. Our study indicates that blocking PI3K pathway activation mediated by HER-2/neu overexpression may be useful in the treatment of breast tumors with HER-2/neu overexpression and wild-type p53.

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Section: Discussionsupporting

confidence: 50%

Downregulation of wild-type p53 protein by HER-2/neu mediated PI3K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy

Ren

et al. 2004

Cell Res

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“…However, pretreatment of cancer cells with genistein followed by docetaxel, cisplatin, or doxorubicin treatment resulted in significantly greater inhibition of cancer cell growth and induction of apoptosis, suggesting that the inactivation of NF-nB by genistein before chemotherapy enhances the antiproliferative and proapoptotic effects of chemotherapeutic agents. Docetaxel, cisplatin, and doxorubicin all have been shown to exert significant cell killing activity in a variety of cancer cells through induction of apoptosis (31)(32)(33). It has been well known that Bcl-2, Bcl-x L , and survivin protect cells from apoptosis whereas p21 WAF1 inhibits cell growth and induces apoptosis (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Nuclear Factor κB by Soy Isoflavone Genistein Contributes to Increased Apoptosis Induced by Chemotherapeutic Agents in Human Cancer Cells

et al. 2005

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Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor KB (NF-KB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-KB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-KB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 Mmol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 Mmol/ L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-KB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-KB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-KB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-KB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers. (Cancer Res 2005; 65(15): 6934-42)

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“…Activated Akt regulates survival by phosphorylating numerous cellular proteins, such as caspase-9 [20], Bad [21], the forkhead family of transcription factors [22], GSK-3β [23], and NF-κB [24]. PI3-K/Akt mediates survival in a variety of cell types, including endothelial cells [16,25], and there is evidence that sustained activation of Akt suppresses doxorubicin-induced apoptosis in gastric adenocarcinoma [26].…”

Section: Introductionmentioning

confidence: 99%

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

Grethe¹,

Coltella²,

Pörn-Ares³

2006

Biochemical and Biophysical Research Communications

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Doxorubicin is the anthracycline with the widest spectrum of antitumor activity, and it has been shown that the antitumor activity is mediated in vivo by selective triggering of apoptosis in proliferating endothelial cells. We studied cultured human endothelial cells and observed that doxorubicin-induced apoptosis was mediated by p38 mitogen-activated protein kinase (MAPK). Doxorubicin-provoked apoptosis was significantly inhibited by expression of dominant negative p38 MAPK or pharmacological inhibition with SB203580.Furthermore, blocking phosphatidylinositol-3-kinase/Akt signaling significantly increased doxorubicin-induced caspase-3 activity and cell death, indicating that Akt is a survival factor in this system. Notably, we also found that doxorubicin-provoked apoptosis included p38 MAPK-mediated inhibition of Akt and Bad phosphorylation. Furthermore, doxorubicinstimulated phosphorylation of Bad in cells expressing dominant negative p38 MAPK was impeded by the inhibition of PI3-K. In addition to the impact on Bad phosphorylation, doxorubicin-treatment caused p38 MAPK-dependent downregulation of Bcl-xL protein.

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Suppression of Adriamycin-induced Apoptosis by Sustained Activation of the Phosphatidylinositol-3′-OH kinase-Akt Pathway

Cited by 29 publications

References 65 publications

Downregulation of wild-type p53 protein by HER-2/neu mediated PI3K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy

Downregulation of wild-type p53 protein by HER-2/neu mediated PI3K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy

Inactivation of Nuclear Factor κB by Soy Isoflavone Genistein Contributes to Increased Apoptosis Induced by Chemotherapeutic Agents in Human Cancer Cells

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

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