|
| Drug or therapy | Protein(s) targeted | Signaling pathways affected |
|
| Imatinib, idarubicin | Survivin | Imatinib and idarubicin inhibited viability and induced apoptosis in cells derived from a Ph+ patient in blast crisis and K562 cells, respectively, through survivin downregulation [144]. |
| Imatinib | Survivin | Enhanced imatinib-mediated apoptosis by modulating reactive oxygen species [147] and using antisense oligonucleotide or dominant-negative survivin [154] in CML cell lines. |
| Microtubule stabilizing agents and flavopiridol vorinostat, MK0457 | Survivin | The combination of microtubule stabilizing agents and the cyclin-dependent kinase inhibitor flavopiridol [149] as well as the cotreatment with vorinostat and the aurora kinase inhibitor [155] led to survivin inhibition and increased apoptosis levels in K562 cells. |
| Sheperdin | Survivin | The survivin inhibitor molecule showed great toxicity against CML and AML cells, with no decrease in viability of phytohemagglutinin-stimulated peripheral blood mononuclear cells [153]. |
| Imatinib | FoxO3a | Imatinib-mediated BCR-ABL inhibition resulted in FoxO3a activation, induction of Bim [156], p27/kip1 [157] and tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) [158], repression of cyclin D4 expression [156] and inhibitor of DNA binding 1 (Id1) [159], and consequent increased apoptosis in CML cell lines. |
| Bortezomib | FoxO3a | Bortezomib treatment was able to restore FoxO3a expression, sensitize imatinib-resistant T315I expressing cells to apoptosis, and inhibit CML-like disease in leukemic mice [160]. |
| IKKB inhibitors | NFκB | The IKKB inhibitors led to the induction of apoptosis in cell lines (K562 and KCL) and bone marrow cells sensitive and resistant to imatinib [161], induced cell death in cell lines BaF3 BCR-ABL wild-type or mutant, including T315I mutation [162], suppressed proliferation of cells from patients with T315I mutation and in vivo experiments resulted in a regression of the tumors in nude mice [163]. |
| Bortezomib | NFκB | Bortezomib reduced proliferation and survival of BCR-ABL-expressing cells, regardless of their sensitivity to imatinib and including the mutant T315I [164], and the combinatory effect with imatinib in CML led to reduced disseminated disease, decreased tumor growth and induced apoptosis in tumor sections [165]. |
| Vincristine | ABCB1 and survivin | Overexpression of ABCB1 and survivin were associated with low apoptosis index induced by vincristine treatment [43]. |
| LQB-118 | ABCB1, survivin and XIAP | LQB-118 overcome resistance phenotype through ABCB1, survivin and XIAP downregulation [166]. |
| Imatinib and nilotinib | SLC22A1, ABCB1 and ABCG2 | K562 cells displayed upregulated levels of SLC22A1, ABCB1, and ABCG2 genes, after exposure to increasing concentrations of imatinib and nilotinib, respectively [167]. |
| Imatinib | SLC22A1, ABCB1 and ABCG2 | Chronic exposure to imatinib increased ABCB1 and ABCG2 at the protein and gene levels, but SLC22A1 expression remained unaltered [168]. |
| Imatinib and vincristine | XIAP and ABCB1 | Simultaneous inhibition of XIAP and ABCB1 in cells that overexpress this efflux pump decreases the resistance to imatinib [129] and vincristine [130]. |
| Imatinib, apicidin and EBT-737 | XIAP | Imatinib-induced apoptosis was found to be associated with XIAP downregulation [121] and could be potentiated when combined with apicidin [122] and EBT-737 [123] in K562 cells and CML progenitors. |
| Etoposide and doxorubicin | XIAP | The downregulation of XIAP expression with antisense oligonucleotides increased apoptosis and enhanced the effects of doxorubicin in K562 cells [128]. |
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