scholarly journals Vitamin E TPGS 1000 Induces Apoptosis in the K562 Cell Line: Implications for Chronic Myeloid Leukemia

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Jazmin Calvo-Alvarez ◽  
Marlene Jimenez-Del-Rio ◽  
Carlos Velez-Pardo
Keyword(s):  
Chronic Myeloid Leukemia ◽  
K562 Cell ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Kinase Inhibitors ◽  
Hematologic Malignancy ◽  
Chromatin Condensation ◽  
K562 Cells ◽  
Signaling Mechanism ◽  
Factor C

Chronic myeloid leukemia (CML) is a hematologic malignancy derived from the myeloid lineage molecularly characterized by t(9;22)(q34;q11) resulting in BCR-ABL1 gene fusion, which is known as Philadelphia (Ph) chromosome. Although tyrosine kinase inhibitors (TKIs) have restored and maintained the quality of life of patients with CML, an important minority of patients become resistant to first-and-second-generation TKIs and require an alternative treatment. The K562 cell (Ph+, p53-/-) line was treated with Vit E TPGS 1000 (20–80 μM) only or with other products of interest (e.g., antioxidant N-acetylcysteine (NAC), specific JNK and caspase-3 inhibitor SP600125, and NSCSI, respectively) for 24 h at 37°C. Cells were analyzed by fluorescence microscopy (FM), flow cytometry (FC), and Western blotting (WB) techniques. We show that TPGS induces apoptosis in K562 cells through H2O2 signaling mechanism comprising the activation of a minimal molecular cascade: the kinase JNK>the transcription factor c-JUN>the activation of BCL-only BH3 proapoptotic protein PUMA>loss of mitochondrial membrane potential (ΔΨm)>activation of caspase-3>chromatin condensation>fragmentation of DNA. Additionally, TPGS oxidizes the stress sensor protein DJ-1-Cys106-SH into DJ-1-Cys106-SO3 and arrested the cell cycle in the S phase. Remarkably, NAC, SP600125, and NSCSI blocked TPGS-induced OS and apoptosis in K562. Since TPGS is safe in mice and humans, it is especially promising for preclinical and clinical CML leukemia research. Our findings support the view that oxidation therapy offers an important opportunity to eliminate CML.

Effect of Dasatinib on Genes Related to Mitotic Catastrophe Pathway in Chronic Myeloid Leukemia Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Sezgi Kipcak ◽  
Buket Ozel ◽  
Cigir B. Avci ◽  
Leila S. Takanlou ◽  
Maryam S. Takanlou ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
K562 Cells ◽  
Mitotic Catastrophe ◽  
Control Group ◽  
Cancer Therapies ◽  
Apoptosis Pathways

Background: Chronic myeloid leukemia (CML), is characterized by a reciprocal translocation t(9;22) and forms the BCR/ABL1 fusion gene, which is called the Philadelphia chromosome. The therapeutic targets for CML patients which are mediated with BCR/ABL1 oncogenic are tyrosine kinase inhibitors such as imatinib, dasatinib, and nilotinib. The latter two of which have been approved for the treatment of imatinib-resistant or intolerance CML patients. Mitotic catastrophe (MC) is one of the non-apoptotic mechanisms which frequently initiated in types of cancer cells in response to anti-cancer therapies; pharmacological inhibitors of G2 checkpoint members or genetic suppression of PLK1, PLK2, ATR, ATM, CHK1, and CHK2 can trigger DNA-damage-stimulated mitotic catastrophe. PLK1, AURKA/B anomalously expressed in CML cells, that phosphorylation and activation of PLK1 occur by AURKB at centromeres and kinetochores. Objective: The purpose of this study was to investigate the effect of dasatinib on the expression of genes in MC and apoptosis pathways in K562 cells. Methods: Total RNA was isolated from K-562 cells treated with the IC50 value of dasatinib and untreated cells as a control group. The expression of MC and apoptosis-related genes were analyzed by the qRT-PCR system. Results: The array-data demonstrated that dasatinib-treated K562 cells significantly caused the decrease of several genes (AURKA, AURKB, PLK, CHEK1, MYC, XPC, BCL2, and XRCC2). Conclusion: The evidence supply a basis to support clinical researches for the suppression of oncogenes such as PLKs with AURKs in the treatment of types of cancer especially chronic myeloid leukemia.

scholarly journals Chronic Myeloid Leukemia and Cesarean Section: The Anesthesiologist’s Point of View

2018 ◽  
Vol 2018 ◽  
pp. 1-3
Author(s):  
Houssam Rebahi ◽  
Mourad Ait Sliman ◽  
Ahmed-Rhassane El Adib
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cesarean Section ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Hematologic Malignancy ◽  
Blast Crisis ◽  
Myeloproliferative Neoplasm ◽  
Point Of View ◽  
Poor Outcomes ◽  
Challenging Situation

Background. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm related to chromosomal reciprocal translocation t(9;22). Tyrosine kinase inhibitors (TKIs) such as imatinib have drastically revolutionized the course and the prognosis of this hematologic malignancy. As we know, the association pregnancy-CML is an infrequent situation. Also the use of TKI in pregnant women is unsafe with a lack of alternatives and effective therapeutic options. Thus its cessation during gestation puts those patients at high risk of developing blast crisis characterized by poor outcomes.Case Report. A 37-year-old pregnant woman, gravida 2, para 2, with a previous cesarean section in 2011, presented to the obstetric unit. Her medical past revealed that she is a newly diagnosed patient with CML managed by TKI during her preconception period. Due to the perilous use of TKI during her pregnancy, a switch to interferon-αadministration was adopted. But after the completion of 36 weeks of gestation, disease progression (relapse with blast crisis), attested by biological worsening, a white blood cell count = 245000/mm3with 32% blasts in the peripheral blood, urged the medical team to opt for cesarean delivery. She underwent general endotracheal anesthesia without any perioperative incidents and gave birth to a healthy newborn. Ten days later, the patient was started on TKI.Discussion. Although data on this specific and challenging situation are limited, this case highlights the difficulties encountered by the anesthesiologists when choosing the accurate anesthetic strategy and how important it is to weigh the risks and benefits inherent to each technique. Above all, taking into consideration the possible central nervous system (CNS) contamination by circulating blast cells when performing spinal or epidural approach is primordial. This potential adverse event (CNS blast crisis) is extremely scarce but it is responsible for high rates of morbidity and mortality.

FLT3, CD32, PU.1, ERG, uPAR, and TAP2 Are Strongly Associated with the Progression of Chronic Myeloid Leukemia and Combination of Small Interference RNA of FLT3 and STI571 Synergistically Induced Apoptosis of K562 Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4237-4237
Author(s):  
Kyung Im Kim ◽  
Kwang-Sung Ahn ◽  
Juwon Park ◽  
Chansu Lee ◽  
Byoung Kook Kim ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Real Time ◽  
Mtt Assay ◽  
Real Time Pcr ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Blast Crisis ◽  
Chronic Phase ◽  
K562 Cells ◽  
Potential Candidate

Abstract To characterize molecular mechanisms by which transition from chronic phase to blast crisis in chronic myeloid leukemia (CML) for developing novel therapeutic targets, we analyzed gene-expression profiles of leukemic cells from 12 patients in chronic phase and 9 patients in blast crisis using a 8.7K cDNA chip. We identified 89 genes that were up-regulated as well as 54 genes that were down-regulated in blast crisis of CML. The expression profile included oncogenes, tumor suppression genes, and human genes encoding proteins involved in transcription, signal transduction, metabolism, cell growth, differentiation, apoptosis and immune functions. 18 genes were selected among the up-regulated group for analysis using real-time PCR. Real-time PCR data indicated that the expression of FLT3 (p < 0.001), CD32 (p < 0.001), ERG (p < 0.001), uPAR (p < 0.001), MAD (p < 0.001) and TAP2 (p < 0.001) showed statistically significant difference between chronic phase and blast crisis. For further analysis, we utilized small hairpin RNAs (shRNAs), also referred to as small interfering RNAs, to target human FLT3. These small interfering RNA constructs significantly inhibited FLT3 expression at mRNA and protein levels in K562 cells. After treating both the FLT3 knockdown cells and control cells (FLT3 wild type) with STI571, MTT assay and the expression patterns of apoptosis related genes (PARP, caspase-3, Bax) were examined. MTT assay and caspase-3 activity assay showed that silencing of the gene for FLT3 significantly reduced cell viability and ultimately facilitated the induction of apoptotic cell death by STI571. These findings uncovered evidence of a complex signaling network operating down-stream of FLT3 that actively contributes to tumor progression. Thus, RNA interference-directed targeting of FLT3 can be a potential candidate anticancer agent in association with STI571 against chronic myeloid leukemia.

PTEN Regulated BCRP/ABCG2 and Side Population Through PI3K/Akt Pathway In Chronic Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5408-5408
Author(s):  
Fang-Fang Huang ◽  
Li Zhang ◽  
Yan-Hui Yu ◽  
Fang-ping Chen ◽  
Hui Zeng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Side Population ◽  
K562 Cells ◽  
Akt Pathway ◽  
Specific Marker ◽  
Pi3k Inhibitor Ly294002

Abstract A small population of cancer stem cells named as “side population (SP)” has been demonstrated to be responsible for many solid tumor maintenance. However, the role of SP in leukemic pathogenesis is still controversial. The resistance of leukemic stem cells in response to targeted therapies such as tyrosine kinase inhibitors (TKIs) results in therapeutic failure or refractory/relapsed disease in chronic myeloid leukemia (CML). The drug pump, ABCG2, is well-known as a specific marker of SP and could be controlled by several pathways including PI3K/Akt. Our data demonstrated that compared to wild type K562 cells, the higher percentage of ABCG2+ cells corresponded to the higher SP fraction in K562/ABCG2 (ABCG2 overexpressing) and K562/IMR (resistance to imatinib) cells, which exhibited enhanced drug resistance along with downregulated PTEN and activated p-Akt. It could be abrogated by both PI3K inhibitor LY294002 and mTOR inhibitor rapamycin. Moreover, in CML patients at accelerated phase/blastic phase (AP/BP), increased SP phenotype rather than ABCG2 expression accompanied with loss of PTEN protein and up-regulation of p-Akt expression was observed. These results suggested that expression of ABCG2 and fraction of SP may be regulated by PTEN through PI3K/Akt pathway, which will be the potentially effective strategy for targeting CML stem cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Antineoplastic Role of STAT5 Inhibition in BCRABL1-Positive Cells Exposed to Pimozide Alone and in Combination with Dasatinib and Ponatinib

2021 ◽  
Author(s):  
Marco Santoro ◽  
Salvatrice Mancuso ◽  
Manlio Tolomeo ◽  
Rosaria Maria Pipitone ◽  
Stefania Grimaudo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cell Lines ◽  
K562 Cell ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Blue Dye ◽  
Association Effect

Background: Though tyrosine kinase inhibitors managed to reach outstanding responses in the treatment of Chronic Myeloid Leukemia, resistance is still a challenging point, occurring in approximately 10–20% of the cases, due to several mechanisms. STAT5 expression has been strictly linked to resistance and disease progression and may thus represent a significant target to overcome resistance to TKI in CML. The aim of the study is to explore the in vitro antineoplastic role of the STAT5 inhibitor Pimozide in association with 2nd and 3rd generation inhibitors on chronic myeloid leukemia cells. Methods: The cytotoxic effect was evaluated by the Trypan blue dye exclusion test. K562 cell lines were exposed to pimozide alone and in association with ponatinib and dasatinib at different concentrations to explore the drugs association effect and the in vitro cytotoxic concentrations. Conclusions: Pimozide showed a synergic effect when associated with ponatinib and dasatinib in survival inhibition of K562 cell lines. This results are of note and pave the way for a possible in vivo associations.

scholarly journals A unique three-way Philadelphia chromosome variant t(4;9;22)(q21;q34;q11.2) in a newly diagnosed patient with chronic phase chronic myeloid leukemia: a case report and review of the literature

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Yuka Torii ◽  
Kana Nanjo ◽  
Tomomi Toubai ◽  
Masashi Hosokawa ◽  
Ryo Sato ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Hematologic Malignancy ◽  
Case Reports ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Chromosome Translocation ◽  
Continuous Treatment ◽  
New Variant

Abstract Background Chronic myeloid leukemia is a hematologic malignancy associated with the fusion of two genes: BCR and ABL1. This fusion results from a translocation between chromosomes 9 and 22, which is called the Philadelphia chromosome. Although the Philadelphia chromosome is present in more than 90% of patients with chronic myeloid leukemia, 5–8% of patients with chronic myeloid leukemia show complex variant translocations. Herein, we report a unique case of a three-way translocation variant in chronic phase chronic myeloid leukemia. Case presentation A 40-year-old Asian male who presented with leukocytosis was diagnosed with chronic phase chronic myeloid leukemia. Cytogenetic karyotyping analysis showed 46,XY,t(4;9;22)(q21;q34;q11.2). He was treated with bosutinib and then changed to dasatinib because of intolerance, and MR4.5 (BCR-ABL/ABL ≦ 0.0032%, international scale) was achieved after 17 months of continuous treatment. Conclusion This was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first successful case treated with tyrosine kinase inhibitors in the world. We summarize previous case reports regarding three-way variant chromosome translocation, t(4;9;22) and discuss how this rare translocation is linked to prognosis.

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

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