2011
DOI: 10.18632/oncotarget.240
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Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

Abstract: The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and prema… Show more

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Cited by 500 publications
(449 citation statements)
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“…Treatment with doxorubicin causes cellular damage through intercalating into DNA, preventing replication and subsequent ROS production during metabolism of the drug. 4,5,7,9 Cells transiently transfected with p53-responsive luciferase vectors were exposed to 100 nM doxorubicin for 24 h. Analysis of luciferase activity revealed that p53 became transcriptionally active in parental 22Rv-1 and LNCaP cells treated with doxorubicin, while most of this activity was abolished in the same cells transfected with p53DD (Fig. 1B).…”
Section: Resultsmentioning
confidence: 97%
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“…Treatment with doxorubicin causes cellular damage through intercalating into DNA, preventing replication and subsequent ROS production during metabolism of the drug. 4,5,7,9 Cells transiently transfected with p53-responsive luciferase vectors were exposed to 100 nM doxorubicin for 24 h. Analysis of luciferase activity revealed that p53 became transcriptionally active in parental 22Rv-1 and LNCaP cells treated with doxorubicin, while most of this activity was abolished in the same cells transfected with p53DD (Fig. 1B).…”
Section: Resultsmentioning
confidence: 97%
“…The mechanism behind these increased or decreased changes in drug sensitivity is proposed to result from DNA damage-causing activation of p53, leading to a halt in cell cycle progression, induction of senescence and/or initiation of apoptosis. 4,7,40,49 Other researchers have found that augmentation of p53 activity in prostate cancer cell lines appear, to only promote cellular apoptosis a small percentage of the time when exposed to radiation. 46 The majority of the effects p53 activity has on the cell is to promote cellular senescence.…”
Section: Resultsmentioning
confidence: 99%
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“…In contrast to other kinase inhibitors MEK inhibitors, including selumetinib, do not compete with ATP binding to inhibit MEK phosphorylation, but rather interfere with MEK binding and the subsequent activation of downstream ERK [191]. Evidence of clinical efficacy for selumetinib monotherapy has been demonstrated in studies of patients with advanced colorectal cancer [192] and melanoma [193].…”
mentioning
confidence: 99%