Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR–CML cell lines?

Abstract

The hallmark of CML (chronic myeloid leukaemia) is the BCR (breakpoint cluster region)–ABL fusion gene. CML evolves through three phases, based on both clinical and pathological features: a chronic phase, an accelerated phase and blast crisis. TKI (tyrosine kinase inhibitors) are the treatment modality for patients with chronic phase CML. The therapeutic potential of the TKI imatinib is affected by BCR–ABL dependent an independent mechanisms. Development of MDR (multidrug resistance) contributes to the overall clinical resistance. MDR involves overexpression of ABC -transporters (ATP-binding-cassette transporter) among other features. MDR studies include the analysis of cancer cell lines selected for resistance. CML blast crisis is accompanied by increased resistance to apoptosis. This work reviews the role played by the influx transporter OCT1 (organic cation transporter 1), by efflux ABC transporters, molecules involved in the modulation of apoptosis (p53, Bcl-2 family, CD95, IAPs (inhibitors of apoptosis protein)], Hh and Wnt/β-catenin pathways, cytoskeleton abnormalities and other features described in leukaemic cells of clinical samples and CML cell lines. An MDR cell line, Lucena-1, generated from K562 by stepwise exposure to vincristine, was used as our model and some potential anticancer drugs effective against the MDR cell line and patients’ samples are presented.

Multidrug resistance in chronic myeloid leukemia

“…For instance, Fas receptors include a highly protected DISC domain inducing apoptosis through activation of caspase cascade. CD95L-stimulated tumor development supports the idea that apoptosis and tumor growth might use different pathways (McGahon et al, 1995;Traer et al, 2012;Rumjanek et al, 2013). IAP is associated with the inhibition of programmed cell death.…”

“…The Bcl-2 antiapoptotic protein family contributes to the intrinsic pathway while the inhibitor of apoptosis (IAP) protein family has a role in regulation of downstream apoptotic processes. Survival mechanisms of CML cells require the coordination of proteins to modulate apoptosis (Rumjanek et al, 2013). The Tp53 tumor suppressor gene encodes the p53 protein and has several functions such as cell cycle regulation, DNA repair, programmed cell death, and genomic stability, making p53 one of the essential molecules in the cell (Naccarati et al, 2012).…”

Ceritinib Enhances the Efficacy of Substrate Chemotherapeutic Agent in Human ABCB1-Overexpressing Leukemia Cells In Vitro, In Vivo and Ex-Vivo

“…Normally, ABCB1 is often distributed in the kidney, pancreas, liver and gut, as a protection mechanism in the human body. Its overexpression has been reported to be related to poor response to chemotherapy and poor overall survival in leukemia patients [11, 12]. Based on this situation, various kinds of drugs including lapatinib [13], cediranib [14], alectinib [15], and gefitinib [16] have been reported to reverse MDR by inhibiting the function of ABCB1.…”

Indole-3-carbinol induces apoptosis of chronic myelogenous leukemia cells through suppression of STAT5 and Akt signaling pathways

“…XIAP was found to be overexpressed in cells from CML patients and associated with an unfavorable prognosis. 39 Similarly, high levels of survivin expression correlated with BCR-ABL expression levels in patients with CML. 40 Our results demonstrated that the mRNA expression levels of XIAP, Bcl-2, and survivin significantly decreased in I3C-treated cells (Figure 3(c)).…”