Management of chronic myeloid leukaemia: current treatment options, challenges, and future strategies

Younes, Salma; Ismail, Mohamed A.; Al-Jurf, Rana; Ziyada, Ayah; Nasrallah, Gheyath K.; Abdulrouf, Palli Valapila; Nagy, M; Zayed, Hatem; Farrell, Thomas S. C.; Sorio, Claudio; Morsi, Hisham; Qoronfleh, M. Walid; Al‐Dewik, Nader

doi:10.1080/16078454.2023.2196866

Cited by 6 publications

(3 citation statements)

References 106 publications

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“…K562 cells are extremely resistant to apoptosis irrespective of the pharmacological compound used for its induction and this feature was shown to be due to the expression of the Bcr-Abl protein [ 61 ]. The tyrosine kinase inhibitors are successfully used as a target therapy for the treatment of CML [ 62 , 63 ]. The possible positive combinatory effects of tyrosine kinase inhibitors and SK/IK channel blockers on the pathophysiological reactions of K562 cells could be a specific goal for future studies.…”

Section: Discussionmentioning

confidence: 99%

Role of Calcium-Activated Potassium Channels in Proliferation, Migration and Invasion of Human Chronic Myeloid Leukemia K562 Cells

et al. 2023

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Calcium-activated potassium channels (KCa) are important participants in calcium signaling pathways due to their ability to be activated by an increase in intracellular free calcium concentration. KCa channels are involved in the regulation of cellular processes in both normal and pathophysiological conditions, including oncotransformation. Previously, using patch-clamp, we registered the KCa currents in the plasma membrane of human chronic myeloid leukemia K562 cells, whose activity was controlled by local Ca2+ entry via mechanosensitive calcium-permeable channels. Here, we performed the molecular and functional identification of KCa channels and have uncovered their role in the proliferation, migration and invasion of K562 cells. Using a combined approach, we identified the functional activity of SK2, SK3 and IK channels in the plasma membrane of the cells. Selective SK and IK channel inhibitors, apamin and TRAM-34, respectively, reduced the proliferative, migratory and invasive capabilities of human myeloid leukemia cells. At the same time, the viability of K562 cells was not affected by KCa channel inhibitors. Ca2+ imaging showed that both SK and IK channel inhibitors affect Ca2+ entry and this could underlie the observed suppression of pathophysiological reactions of K562 cells. Our data imply that SK/IK channel inhibitors could be used to slow down the proliferation and spreading of chronic myeloid leukemia K562 cells that express functionally active KCa channels in the plasma membrane.

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Section: Discussionmentioning

confidence: 99%

Role of Calcium-Activated Potassium Channels in Proliferation, Migration and Invasion of Human Chronic Myeloid Leukemia K562 Cells

et al. 2023

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“…The first was imatinib (IMA), followed by the second generation-dasatinib (DAS), nilotinib (NIL), and bosutinib (BOS)-and the third generation, ponatinib (PON). 71 More recently, allosteric inhibitors of BCR-ABL, such as asciminib (ASC) and GNF-5, have been designed. These inhibitors bind to the myristoyl binding pocket in the kinase domain, inactivating BCR-ABL activity by preventing its bioactive conformation.…”

Section: Inhibitors Of Bcr-ablmentioning

confidence: 99%

“…74 In addition to the adverse effects resulting from the administration of these TKIs, there is also the possibility of resistance occurring that may preclude the use of these types of inhibitors, particularly the T315I mutation. 71…”

Section: Inhibitors Of Bcr-ablmentioning

confidence: 99%

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Vicente,

Salvador

2024

MedComm

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Leukemia is a heterogeneous group of life‐threatening malignant disorders of the hematopoietic system. Immunotherapy, radiotherapy, stem cell transplantation, targeted therapy, and chemotherapy are among the approved leukemia treatments. Unfortunately, therapeutic resistance, side effects, relapses, and long‐term sequelae occur in a significant proportion of patients and severely compromise the treatment efficacy. The development of novel approaches to improve outcomes is therefore an unmet need. Recently, novel leukemia drug discovery strategies, including targeted protein degradation, have shown potential to advance the field of personalized medicine for leukemia patients. Specifically, PROteolysis‐TArgeting Chimeras (PROTACs) are revolutionary compounds that allow the selective degradation of a protein by the ubiquitin–proteasome system. Developed against a wide range of cancer targets, they show promising potential in overcoming many of the drawbacks associated with conventional therapies. Following the exponential growth of antileukemic PROTACs, this article reviews PROTAC‐mediated degradation of leukemia‐associated targets. Chemical structures, in vitro and in vivo activities, pharmacokinetics, pharmacodynamics, and clinical trials of PROTACs are critically discussed. Furthermore, advantages, challenges, and future perspectives of PROTACs in leukemia are covered, in order to understand the potential that these novel compounds may have as future drugs for leukemia treatment.

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Safety Pharmacology in the Era of Precision Medicine

Al-Mahayri,

Nagy

2024

Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

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Management of chronic myeloid leukaemia: current treatment options, challenges, and future strategies

Cited by 6 publications

References 106 publications

Role of Calcium-Activated Potassium Channels in Proliferation, Migration and Invasion of Human Chronic Myeloid Leukemia K562 Cells

Role of Calcium-Activated Potassium Channels in Proliferation, Migration and Invasion of Human Chronic Myeloid Leukemia K562 Cells

PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives

Safety Pharmacology in the Era of Precision Medicine

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