Leukaemic stem cells: Drug resistance, metastasis and therapeutic implications
Faculty of Medicine, SEGi University, No. 9, Jalan Tecknologi, Taman Sains Selangor, Kota Damansara, PJU 5, 47810 Petaling Jaya, Selangor, Malaysia. The Malaysian journal of pathology
Although there have been many new developments in the treatment of leukaemia with the use of new anti-leukaemic agents and stem cell transplantation, drug resistance and treatment failure remain a great challenge for the attending physician. Several studies have suggested that leukaemic stem cells (LSCs) play a pivotal role in chemoresistance and metastasis and the mechanisms by which these cells do so have also been elucidated. There is increasing evidence to show that there exists a large pool of therapeutic targets in LSCs and that the eradication of these cells is feasible with some promising results. This article gives an overview of different types of cancer stem cells (CSCs) derived from various types of leukaemia, the mechanisms by which LSCs contribute to drug resistance and metastasis and some recent advances in targeted therapy against LSCs.
Available from: Jia-Jie Chen
- "Although chemotherapy results in clinical remission for AML, drug resistance still represents a huge challenge to achieve effective treatment, especially in relapsed or refractory AML patients , . Cytostatic drug resistance occurs through different mechanisms, including induction of drug detoxification , the over-expression of oncogene or inactivation of tumor suppressor gene , , metabolic disturbance , , as well as existence of leukemia stem cells . Still, the exact mechanisms of drug resistance in leukemia have not been fully investigated. "
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ABSTRACT: Nowadays, drug resistance still represents a major obstacle to successful acute myeloid leukemia (AML) treatment and the underlying mechanism is not fully elucidated. Here, we found that high expression of c-Myc was one of the cytogenetic characteristics in the drug-resistant leukemic cells. c-Myc over-expression in leukemic cells induced resistance to chemotherapeutic drugs, enhanced colony formation capacity and inhibited cell differentiation induced by all-trans retinoic acid (ATRA). Meanwhile, inhibition of c-Myc by shRNA or specific c-Myc inhibitor 10058-F4 rescued the sensitivity to cytotoxic drugs, restrained the colony formation ability and promoted differentiation. RT-PCR and western blotting analysis showed that down-regulation of C/EBPβ contributed to the poor differentiation state of leukemic cells induced by c-Myc over-expression. Importantly, over-expression of C/EBPβ could reverse c-Myc induced drug resistance. In primary AML cells, the c-Myc expression was negatively correlated with C/EBPβ. 10058-F4, displayed anti-proliferative activity and increased cellular differentiation with up-regulation of C/EBPβ in primary AML cells. Thus, our study indicated that c-Myc could be a novel target to overcome drug resistance, providing a new approach in AML therapy.
PLoS ONE 08/2014; 9(8):e105381. DOI:10.1371/journal.pone.0105381 · 3.23 Impact Factor
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ABSTRACT: Radiotherapy and adjuvant cisplatin (DDP) chemotherapy are standard approaches used in the treatment of nasopharyngeal carcinoma (NPC). However, resistance to chemotherapy has recently become more common, resulting in the failure of this combination therapy for NPC. The aim of the present study was to assess the cellular morphology, motility and molecular changes in DDP-resistant NPC cells in relation to epithelial-mesenchymal transition (EMT). CNE2 cells were continuously exposed to increasing doses of DDP to establish a stable cell line resistant to DDP (CNE2/DDP cells). The human NPC cell lines, HNE1, CNE2, HNE1/DDP and CNE2/DDP, were used to examine the association between chemoresistance and the acquisition of an EMT-like phenotype of cancer cells. The DDP-resistant cells were less sensitive than the HNE1 cells to treatment with DDP, and were shown by a cell viability assay, western blot analysis and qRT-PCR to have acquired chemoresistance. The HNE1/DDP cells examined by wound healing and Transwell Boyden chamber assays exhibited an increased migration and invasion potential. The DDP-resistant cells exhibited morphological and molecular changes consistent with EMT, as observed by western blot analysis and qRT-PCR. These changes included becoming more spindle-like in shape, a loss of polarity and formation of pseudopodia, the downregulation of E-cadherin and β-catenin and the upregulation of vimentin, ﬁbronectin and matrix metalloproteinase (MMP)-9. Moreover, the levels of the EMT-related transcription factors, Snail, Slug, Twist and zinc finger E-box binding homeobox 1 (ZEB1), were higher in the DDP‑resistant NPC cells. These data suggest that the development of DDP resistance of NPC cells is accompanied by inducible EMT-like changes with an increased metastatic potential in vitro. Further elucidation of the association between resistance to DDP and EMT may facilitate the future development of novel therapeutic approaches for the treatment of chemoresistant tumors.
International Journal of Molecular Medicine 10/2013; 33(1). DOI:10.3892/ijmm.2013.1538 · 2.09 Impact Factor
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ABSTRACT: Acute myeloid leukaemia (AML) is a neoplasm originating in early haematopoietic progenitor cells. Each AML clone contains a subpopulation of leukaemic stem cells (LSCs). LSCs have the capacity to repopulate AML in NOD/SCID mice and regrow leukaemia in patients after remission period. LSCs are characterized by CD34+CD38-Lin-CD33+/-CD123+ immunophenotype. The currently available data show that LSCs play a pivotal role in drug resistance. Many studies and clinical trials are being conducted to eradicate LSCs using different forms of target therapy.
Acta haematologica Polonica 04/2014; 45(2). DOI:10.1016/j.achaem.2014.04.002
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