Medication this kind of as doxorubicin and taxol are beneficial from the therapy of numerous cancers, although in some cases drug resistance develops following prolonged treatment. Doxorubicin and taxol target cellular events, such as DNA replication and cell division, that are frequently downstream of the targets of signal transduction pathway inhibitors. Chemotherapeutic medication can activate the Ras/Raf/MEK/ERK pathway by diverse mechanisms . Drugs such as doxorubicin can activate p53 which might lead to enhanced expression with the discoidin domain receptor , which in turn can result in Raf/MEK/ERK pathway activation. Activated ERK can phosphorylate p53 and regulate its action. Doxorubicin may also activate the calcium calmodulin dependent kinase cascade via reactive oxygen species . Activation of this cascade may also lead to activation in the Raf/MEK/ERK cascade. Activation of this cascade can result in the transcription of genes such as XRCC1 and ERCC1 which are associated with DNA fix and cause drug resistance . Taxols also can stimulate activation within the Raf/MEK/ERK cascade and bring about their greater association with proteins involved in cell division . As a result, by combining classical chemotherapy with targeted therapy, it may be feasible to boost toxicity, even though decreasing the prescribed concentrations of classical chemotherapeutics Masitinib selleckchem important for useful elimination within the tumor . As we have now previously discussed, activation in the Raf/MEK/ERK cascade can alter the action and subcellular localization of countless proteins that perform critical roles in apoptotic cascades.
Also the Raf/ MEK/ERK cascade can regulate the transcription of a lot of critical genes associated with cell cycle progression, development and differentiation. A phase II trial demonstrated the blend of sorafenib and doxorubicin improves progression-free and overall survival of patients with advanced HCC . Additionally, a phase II trial is at the moment recruiting individuals to find out the progression-free survival of sorafenib plus tegafur/uracil to the therapy of sophisticated or metastatic HCC. As pointed out previously, a side result of some chemotherapeutic medication, such as paclitaxel, would be the induction on the Raf/MEK/ERK Motesanib pathways. Activation of this pathway can beneath specific conditions market proliferation and prevent apoptosis. Also the PI3K/PTEN/ Akt/mTOR pathway can modulate the Raf/MEK/ERK pathway and altering MEK exercise can have opposing results on diverse cell styles . Combining paclitaxel remedy with PI3K inhibitors enhances apoptosis and inhibits growth of ovarian carcinoma cell lines, and this could possibly are actually mediated in portion by suppression of inhibitory phosphorylation of Raf by Akt .