Table 1.

Anticancer drugs sensitize CML cells by targeting IAPs, drug transporters, NFκB and FoxO proteins.

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].

AML: acute myeloid leukemia, CML: chronic myeloid leukemia; IAPs: inhibitor apoptosis proteins.