The inhibition of ERK/MAPK not the activation of JNK/SAPK is primarily required to induce apoptosis in chronic myelogenous leukemic K562 cells

EGF activates an inducible survival response via the RAS-> Erk-1/2 pathway to counteract interferon-α-mediated apoptosis in epidermoid cancer cells

“…27 It has also been demonstrated that Erk-1/2 antagonize apoptosis in several experimental models. 22,[28][29][30] We have previously reported that IFNa induces growth inhibition and increases the expression and function of EGF-R in human epidermoid cancer cells. 23,24 Moreover, we have demonstrated that the growth inhibition induced by IFNa is, at least in part, because of the apoptosis triggered by a stress response leading to the activation of JNK-1, and that EGF antagonizes growth inhibition, apoptosis and the biochemical events induced by the cytokine.…”

Coadministration of UCN-01 with MEK1/2 Inhibitors Potently Induces Apoptosis in

“…In fact, despite the activation of survival signaling pathways downstream of Bcr/Abl, [5][6][7][8][9] Bcr/Abl + leukemia cells were at least as sensitive to this drug combination as other malignant hematopoietic cells lacking this gene rearrangement. 25,43 Interestingly, while the cytoprotective MAP kinase pathway has been reported to be a downstream target of Bcr/Abl, 8 ERK activation was clearly observed in Bcr/Abl + cells exposed to the Chk1 inhibitor UCN-01. Such a finding suggests that engagement of the ERK cascade represents a general response of malignant hematopoietic cells to Chk1 inhibition and the resulting activation(dephosphorylation) of p34 cdc2 .…”

“…[3][4] Constitutive activation of the Bcr/Abl kinase results in activation/increased expression of a variety of downstream targets, including Akt, NFκB, ERK (extracellular-regulated kinase), STAT5, Bcl-x L , among others. [5][6][7][8][9] In addition to providing cells with a proliferative advantage, the Bcr/Abl kinase renders CML cells relatively resistant to multiple conventional cytotoxic agents. 10 Recently, the treatment of CML has been profoundly influenced by the introduction of STI571 (imatinib mesylate; Gleevec), a tyrosine kinase inhibitor that inhibits Bcr/Abl, c-Kit, PDGF, and other kinases.…”

Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571

“…Cytoplasmic BCR/ABL proteins (Dhut et al, 1990) exert their oncogenic potential in cooperation with numerous cytoplasmic and nuclear effectors (Raitano et al, 1997;Sattler and Salgia, 1997). Several major signaling pathways are engaged by BCR/ABL leading to the activation of such proteins as: RAS (Goga et al, 1995;Pendergast et al, 1993;Puil et al, 1994;Sawyers et al, 1995;Skorski et al, 1994), MAPK (Kang et al, 1999(Kang et al, , 2000, STAT5 (de Groot et al, 1999;Horita et al, 2000;Nieborowska-Skorska et al, 1999;Sillaber et al, 2000) and PI-3k (Neshat et al, 2000;Skorski et al, 1995aSkorski et al, , 1997aVarticovski et al, 1991). RAS, MAPK and STAT5 are important for the growth of normal and Ph 1 -positive hematopoietic cells (de Groot et al, 1999;Kolonics et al, 2001;Skorski et al, 1992Skorski et al, , 1994Teglund et al, 1998;Welham et al, 1992).…”