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Leukemia chemoresistance

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https://www.readbyqxmd.com/read/29017371/cytarabine-and-daunorubicin-for-the-treatment-of-acute-myeloid-leukemia
#1
Tracy Murphy, Karen Wl Yee
Acute myeloid leukemia (AML) is the most common acute forms of leukemia in adults. It has a poor long-term survival with a high relapse rate and at relapse, is commonly resistant to available therapies. The current combination of daunorubicin (DNR) for three days and cytarabine (Ara-C) as a continuous infusion for seven days, more commonly known as '3+7' has remained essentially unaltered over the last forty-four years and remains the standard induction regimen internationally. Areas covered: This paper will briefly review clinically important trials related to '3+7'...
October 11, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28939105/protein-kinase-c-eta-regulates-mcl-1-level-via-erk1
#2
Deepanwita Pal, Alakananda Basu
Protein kinase C (PKC)-eta (PKCη) is a member of the novel category of PKC family. It is overexpressed in breast cancer and was shown to inhibit apoptosis and contribute to chemoresistance. Since the anti-apoptotic Bcl-2 family protein myeloid cell leukemia-1 (Mcl-1) plays an important role in breast cancer cell survival and chemoresistance, we investigated if PKCη regulates Mcl-1 level. Silencing of PKCη decreased Mcl-1 in several breast cancer cells, including MCF-7 and T47D cells. PKCη depletion had no effect on MCL1 mRNA but the decrease in Mcl-1 by PKCη knockdown was blocked by proteasomal inhibitors, such as MG132 and lactacystin...
September 20, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28923207/eviction-from-the-sanctuary-development-of-targeted-therapy-against-cell-adhesion-molecules-in-acute-lymphoblastic-leukemia
#3
REVIEW
Sonali P Barwe, Anthony Quagliano, Anilkumar Gopalakrishnapillai
Acute lymphoblastic leukemia (ALL) is a malignant hematological disease afflicting hematopoiesis in the bone marrow. While 80%-90% of patients diagnosed with ALL will achieve complete remission at some point during treatment, ALL is associated with high relapse rate, with a 5-year overall survival rate of 68%. The initial remission failure and the high rate of relapse can be attributed to intrinsic chemoprotective mechanisms that allow persistence of ALL cells despite therapy. These mechanisms are mediated, at least in part, through the engagement of cell adhesion molecules (CAMs) within the bone marrow microenvironment...
April 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28917156/tgf%C3%AE-1-synergizes-with-flt3-ligand-to-induce-chemoresistant-quiescence-in-acute-lymphoblastic-leukemia-with-mll-gene-rearrangements
#4
M Tamai, Y Furuichi, S Kasai, N Ando, D Harama, K Goi, T Inukai, K Kagami, M Abe, H Ichikawa, K Sugita
Fms-like tyrosine kinase 3 (FLT3) is highly expressed in mixed-lineage leukemia (MLL) gene-rearranged acute lymphoblastic leukemia (MLL+ALL) with a dismal prognosis. We previously reported that FLT3 ligand (FL) stimulation induced cell cycle arrest in MLL+ALL cells leading to resistance against anti-leukemic agents. Given that FL stimulation enhanced transforming growth factor (TGF)β1 mRNA levels in MLL+ALL cells, we extensively examined the effect of TGFβ1 on the cell cycle progression and chemosensitivity in MLL+ALL cells, and found that TGFβ1 stimulation induced MLL+ALL cells into cell cycle arrest resistant to arabinosyl cytosine; its effect was markedly enhanced in synergy with FL...
October 2017: Leukemia Research
https://www.readbyqxmd.com/read/28881725/nurse-like-cells-promote-cll-survival-through-lfa-3-cd2-interactions
#5
Frédéric Boissard, Marie Tosolini, Laetitia Ligat, Anne Quillet-Mary, Frederic Lopez, Jean-Jacques Fournié, Loic Ysebaert, Mary Poupot
In the tumoral micro-environment (TME) of chronic lymphocytic leukemia (CLL), nurse-like cells (NLC) are tumor-associated macrophages which play a critical role in the survival and chemoresistance of tumoral cells. This pro-survival activity is known to involve soluble factors, but few data are available on the relative role of cells cross-talk. Here, we used a transcriptome-based approach to systematically investigate the expression of various receptor/ligand pairs at the surface of NLC/CLL cells. Their relative contribution to CLL survival was assessed both by fluorescent microscopy to identify cellular interactions and by the use of functional tests to measure the impact of uncoupling these pairs with blocking monoclonal antibodies...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28842696/adhesion-to-stromal-cells-mediates-imatinib-resistance-in-chronic-myeloid-leukemia-through-erk-and-bmp-signaling-pathways
#6
Atul Kumar, Jina Bhattacharyya, Bithiah Grace Jaganathan
Chronic myeloid leukemia (CML) is characterized by abnormal proliferation of myeloid cells which when untreated leads to bone marrow failure. Imatinib mesylate (IM) is the first line of therapy for treatment of CML and results in remission in most cases. However, a significant percentage of patients develop chemoresistance to IM, which might be due to the presence of chemoresistant cells in the bone marrow. In the current study, we explored the role of cell-cell interaction of CML cells with the bone marrow stromal cells in the development of chemoresistance in CML...
August 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28807161/phytochemical-modulation-of-apoptosis-and-autophagy-strategies-to-overcome-chemoresistance-in-leukemic-stem-cells-in-the-bone-marrow-microenvironment
#7
Helen C Owen, Sandra Appiah, Noor Hasan, Lucy Ghali, Ghada Elayat, Celia Bell
Advances in scientific research and targeted treatment regimes have improved survival rates for many cancers over the past few decades. However, for some types of leukemia, including acute lymphoblastic and acute myeloid leukemia, mortality rates have continued to rise, with chemoresistance in leukemic stem cells (LSCs) being a major contributing factor. Most cancer drug therapies act by inducing apoptosis in dividing cells but are ineffective in targeting quiescent LSCs. Niches in the bone marrow, known as leukemic niches, behave as "sanctuaries" where LSCs acquire drug resistance...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28775123/tlr9-stimulation-can-induce-ikappabzeta-expression-and-igm-secretion-in-chronic-lymphocytic-leukemia-cells
#8
Eleonora Fonte, Maria Giovanna Vilia, Daniele Reverberi, Ilenia Sana, Lydia Scarfò, Pamela Ranghetti, Ugo Orfanelli, Simone Cenci, Giovanna Cutrona, Paolo Ghia, Marta Muzio
Chronic lymphocytic leukemia cells strongly depend on external stimuli for their survival. Both antigen receptor and co-stimulatory receptors including Toll-Like Receptors can modulate viability and proliferation of leukemic cells. Toll-Like Receptors ligands, and particularly the TLR9 ligand CpG, mediate heterogeneous responses in patient samples reflecting their clinical course. However, the molecular framework of the key signaling events underlying such heterogeneity is undefined. We focused our studies on a subset of chronic lymphocytic leukemia cases characterized by expression of CD38 and unmutated immunoglobulin genes, that respond to CpG with enhanced metabolic cell activity...
August 3, 2017: Haematologica
https://www.readbyqxmd.com/read/28751770/enhancing-venetoclax-activity-in-acute-myeloid-leukemia-by-co-targeting-mcl1
#9
T-C Teh, N-Yn Nguyen, D M Moujalled, D Segal, G Pomilio, S Rijal, A Jabbour, K Cummins, K Lackovic, P Blombery, E Thompson, P G Ekert, G Lessene, S P Glaser, D C S Huang, A W Roberts, M A Guthridge, A H Wei
Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the BCL-2 family of proteins is an attractive option to combat chemoresistance in leukemia. Pre-clinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (e.g. venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase anti-leukemic efficacy in a TP53 dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53...
July 28, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28748730/therapeutic-targeting-of-leukemic-stem-cells-in-acute-myeloid-leukemia-the-biological-background-for-possible-strategies
#10
REVIEW
Øystein Bruserud, Elise Aasebø, Maria Hernandez-Valladares, Galina Tsykunova, Håkon Reikvam
Acute myeloid leukemia (AML) is an aggressive malignancy, caused by the accumulation of immature leukemic blasts in blood and bone marrow. There is a relatively high risk of chemoresistant relapse even for the younger patients who can receive the most intensive antileukemic treatment. Treatment directed against the remaining leukemic and preleukemic stem cells will most likely reduce the risk of later relapse. Areas covered: Relevant publications were identified through literature searches. The authors searched for original articles and recent reviews describing (i) the characteristics of leukemic/preleukemic stem cells; (ii) the importance of the bone marrow stem cell niches in leukemogenesis; and (iii) possible therapeutic strategies to target the preleukemic/leukemic stem cells...
October 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28744141/the-translational-expression-of-abca2-and-abca3-is-a-strong-prognostic-biomarker-for-multidrug-resistance-in-pediatric-acute-lymphoblastic-leukemia
#11
Narges Aberuyi, Soheila Rahgozar, Zohreh Khosravi Dehaghi, Alireza Moafi, Andrea Masotti, Alessandro Paolini
PURPOSE: The aim of this work was to study the correlation between the expressions of the ABCA2 and ABCA3 genes at the mRNA and protein levels in children with acute lymphoblastic leukemia (ALL) and the effects of this association on multidrug resistance (MDR). MATERIALS AND METHODS: Sixty-nine children with de novo ALL and 25 controls were enrolled in the study. Mononuclear cells were isolated from the bone marrow. The mRNA levels of ABCA2 and ABCA3 were measured by real-time polymerase chain reaction (PCR)...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28737756/overexpression-of-zinc-finger-protein-687-enhances-tumorigenic-capability-and-promotes-recurrence-of-hepatocellular-carcinoma
#12
T Zhang, Y Huang, W Liu, W Meng, H Zhao, Q Yang, S-J Gu, C-C Xiao, C-C Jia, B Zhang, Y Zou, H-P Li, B-S Fu
Zinc finger protein 687 (ZNF687), identified as a C2H2 zinc finger protein, has been found to be mutated and upregulated in giant cell tumor of bone and acute myeloid leukemia, suggesting an oncogenic role for ZNF687 in cancer. However, the clinical significance and precise role of ZNF687 in cancer progression are largely unknown. Herein, we report that ZNF687 was markedly upregulated in hepatocellular carcinoma (HCC) cell lines and HCC tissues, and was significantly correlated with relapse-free survival in HCC...
July 24, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28693180/soluble-urokinase-type-plasminogen-activator-receptor-and-urokinase-type-plasminogen-activator-receptor-contribute-to-chemoresistance-in-leukemia
#13
Hong Guo, Lan-Xia Zhou, Haizhen Ma, Bei Liu, Juan Cheng, Yun-Yun Ma, Li Zhao
The soluble urokinase-type plasminogen activator receptor (suPAR) and the urokinase-type plasminogen activator receptor (uPAR) have been proposed as useful biomarkers of tumor progression. Recently, suPAR was associated with chemoresistance in lung cancer. However, its clinical significance in leukemia has not previously been investigated. The present study examined the plasma levels of suPAR and the expression of the uPAR on bone marrow (BM) cells in 86 patients with leukemia at diagnosis prior to chemotherapy and 26 normal subjects (control group)...
July 2017: Oncology Letters
https://www.readbyqxmd.com/read/28681618/regulation-of-p53-and-survivin-by-prodigiosin-compound-derived-from-serratia-marcescens-contribute-to-caspase-3-dependent-apoptosis-in-acute-lymphoblastic-leukemia-cells
#14
M R Sam, R S Pourpak
Tumor suppressor p53 and proto-oncogene survivin are challenging targets for anticancer drugs in acute lymphoblastic leukemia (ALL) which are associated with chemoresistance. Yet, no p53 and survivin-modulating drug with low toxicity and high efficacy has been approved for clinical application in ALL. Consequently, the search for novel compounds which target p53 or survivin is needed to further advance ALL treatment. Prodigiosin, a secondary metabolite of Serratia marcescens induces apoptosis in cancer cells with no toxicity on normal cells...
January 1, 2017: Human & Experimental Toxicology
https://www.readbyqxmd.com/read/28670893/osteopontin-b-and-c-isoforms-molecular-candidates-associated-with-leukemic-stem-cell-chemoresistance-in-acute-myeloid-leukemia
#15
Akram Mirzaei, Saeed Mohammadi, Seyed H Ghaffari, Mohsen Nikbakht, Davood Bashash, Kamran Alimoghaddam, Ardeshir Ghavamzadeh
Despite impressive advances in therapeutic approaches, long-term survival with acute myeloid leukemia (AML) is low as a result of treatment resistance and frequent relapse. Among multitude oncogenic proteins involved in acquisition of a chemo-resistanr phenotype, osteopontin (OPN) recently has attracted marked attention. In spite of the well-defined association between OPN expression and cure rate with solid tumors, there is a scarcity of information on any role of this protein in AML cases. Based on the critical role of OPN in cell survival, it seems reasonable to hypothesize that isoform expression levels may impact on regulation of apoptosis in AML cells in response to conventional chemotherapeutic drugs and its relation to relapse...
June 25, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28654259/new-inhibitor-targeting-signal-transducer-and-activator-of-transcription-5-stat5-signaling-in-myeloid-leukemias
#16
Ludovic Juen, Marie Brachet-Botineau, Cécile Parmenon, Jérôme Bourgeais, Olivier Hérault, Fabrice Gouilleux, Marie-Claude Viaud-Massuard, Gildas Prié
Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5...
July 27, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28647567/stearoyl-coa-desaturase-regulates-sorafenib-resistance-via-modulation-of-er-stress-induced-differentiation
#17
Mark Kin Fai Ma, Eunice Yuen Ting Lau, Doris Hoi Wing Leung, Jessica Lo, Nicole Pui Yu Ho, Lily Kwan Wai Cheng, Stephanie Ma, Chi Ho Lin, John A Copland, Jin Ding, Regina Cheuk Lam Lo, Irene Oi Lin Ng, Terence Kin Wah Lee
BACKGROUND & AIMS: We investigated the functional role and clinical significance of stearoyl-CoA desaturase-1 (SCD1) mediated endoplasmic reticulum (ER) stress in regulating liver tumor-initiating cells (T-ICs) and sorafenib resistance, with the aim of developing a novel therapeutic strategy against hepatocellular carcinomas (HCCs). METHODS: We evaluated the clinic-pathological relevance of SCD1 and its correlation with sorafenib resistance in large cohorts of HCC clinical samples by qPCR and immunohistochemical analyses...
June 22, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28641630/-sdf-1%C3%AE-cxcr4-mediated-drug-resistance-can-be-reversed-by-ibrutinib-in-acute-lymphoblastic-leukemia
#18
Yuan-Yuan Hu, Shan-Dong Tao, Jing-Jing Ma, Li-Tao Zhou, Yue Chen, Liang Yu
OBJECTIVE: To explore the effect of Ibrutinib on the chemoresistance mediated by SDF-1α/CXCR4 axis in ALL cells. METHODS: Flow cytometry was used to detect the apoptosis of cell line and expression of surface membrane CXCR4, Western blot was used to determine the expression level of CXCR4, ERK and Bcl-xL proteins, qPCR was used to assay the mRNA level of CXCR4. RESULTS: Ibrutinib enhanced the apoptosis induced by adriamycin(ADR) (17.100±4...
June 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28626216/therapeutic-effects-of-csf1r-blocking-antibodies-in-multiple-myeloma
#19
Q Wang, Y Lu, R Li, Y Jiang, Y Zheng, J Qian, E Bi, C Zhang, J Hou, S Wang, Q Yi
Our previous studies showed that macrophages (MФs), especially myeloma-associated MФs (MAMs) induce chemoresistance in human myeloma. Here we explored the potential of targeting MФs, by using colony-stimulating factor 1 receptor (CSF1R)-blocking mAbs, to treat myeloma. Our results showed that CSF1R blockade specifically inhibited the differentiation, proliferation and survival of murine M2 MФs and MAMs, and repolarized MAMs towards M1-like MФs in vitro. CSF1R blockade alone inhibited myeloma growth in vivo, by partially depleting MAMs, polarizing MAMs to the M1 phenotype, and inducing a tumor-specific cytotoxic CD4(+) T cell response...
June 19, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28599501/microrna-217-inhibits-cell-proliferation-and-enhances-chemosensitivity-to-doxorubicin-in-acute-myeloid-leukemia-by-targeting-kras
#20
Yi Xiao, Taoran Deng, Changliang Su, Zhen Shang
Acute myeloid leukemia (AML) is a heterogeneous malignant disorder derived from the myeloid hematopoietic cells that accounts for ~80% of all adult acute leukemia. Numerous studies have shown that drug resistance not only exists against conventional chemotherapeutic drugs, but also limits the efficacy of new biological agents. Therefore, it is important to identify the mechanisms behind chemoresistance and seek therapeutic strategies to enhance efficacy in AML chemotherapy. MicroRNA (miR)-217 has been recognized as a tumor suppressor that is downregulated in various types of cancer, however the mechanisms behind the expression and function of miR-217 in AML have not yet been recognized...
June 2017: Oncology Letters
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