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.

Figure 1. Mechanisms involved in the MDR phenotype

Figure 2. Signalling pathways involved in MDR phenotype: the case of Lucena-1 cell line

A model of crosstalk among the pathways and their related proteins that lead to the MDR phenotype in Lucena-1 cells. Based on the canonical pathways at KEGG database [119] for the transcription factors of the ABCB1 gene described by Scotto [120] and the reports cited within this review. FasR, Fas [TNF (tumour necrosis factor) receptor superfamily, member 6]; TNFR, tumour necrosis factor receptor superfamily, member 1; FADD, Fas (TNFRSF6)-associated via death domain; TRADD; TNFRSF1A-associated via death domain; RIP1, Receptor (TNFRSF)-interacting serine–threonine kinase 1; TRAF2, TNF receptor-associated factor 2; CASP 10, caspase 10, apoptosis-related cysteine peptidase; CASP 8, caspase 8, apoptosis-related cysteine peptidase; CASP 3, caspase 3, apoptosis-related cysteine peptidase; CASP 7, caspase 7, apoptosis-related cysteine peptidase; CASP 9, caspase 9, apoptosis-related cysteine peptidase; Bid, BH3 interacting domain death agonist; BCL-2, B-cell CLL/lymphoma 2; Bcl-X_L, BCL2-like 1; Smac/Diablo, diablo, IAP-binding mitochondrial protein; XIAP, X-linked inhibitor of apoptosis; Survivin, baculoviral IAP repeat containing 5; cIAP-1, baculoviral IAP repeat containing 2; cIAP-2, baculoviral IAP repeat containing 3; NF-κB, nuclear factor of kappa light polypeptide gene enhancer in B-cells; HIF1, hypoxia inducible factor 1, alpha subunit; AP1, Transcription factors composed of members of the Jun and Fos families; TCEF/LEF, transcription factors of the T-cell factor/lymphoid enhancer factor family; B-catenin, catenin (cadherin-associated protein), beta 1; CYT C, cytochrome c, somatic; APAF1, apoptotic peptidase activating factor 1; IκB, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IKK, kinases of inhibitor of kappa light polypeptide gene enhancer in B-cells; Wnt, wingless-type MMTV integration site family; LRP5/6, low-density lipoprotein receptor-related protein 5 and protein 6; Frizzled, receptors of frizzled family; DVL, dishevelled, dsh homologue 1 (Drosophila); PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; BCR–ABL, fusion protein encoded by BCR and c-abl oncogene 1, non-receptor tyrosine kinase (ABL) genes; JNK, mitogen-activated protein kinase 8; GSK3B, glycogen synthase kinase 3 beta; LMW-PTP, low molecular weight protein tyrosine phosphatases; RAS, Ras superfamily of proteins; ERK (extracellular-signal-regulated kinase), mitogen-activated protein kinase 1; GLI,GLI family zinc finger; OCT-4,POU class 5 homeobox 1; CEPBeta CCAAT/enhancer binding protein (C/EBP), beta.