Inhibition of crosstalk between Bcr-Abl and PKC signaling by PEITC, augments imatinib sensitivity in chronic myelogenous leukemia cells

Roy, Madhumita; Sarkar, Ruma; Mukherjee, Arup; Mukherjee, Sutapa

doi:10.1016/j.cbi.2015.10.004

Cited by 17 publications

(14 citation statements)

References 28 publications

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“…Additionally, PKC provides anti-apoptotic signaling by activation of the NF-κB and Bcl2 signaling axis [19] and lies downstream of BCR-ABL. A recent study indicated that PKC inhibition in BCR-ABL expressing cells was synergistic with tyrosine kinase inhibition [17]. PKC inhibition via the DAG mimetic moiety of KPC34 combined with the induction of DNA damage by the gemcitabine monophosphate moiety may further explain this hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…The novel members (PKCδ, ε, η, and θ) require only DAG or PS for activity. PKC lies immediately downstream of PLC which is in turn activated by multiple key signaling pathways in ALL including BCR-ABL [15–17]. The α and β family members are highly expressed in ALL cell lines and primary patient samples and targeting these kinases is cytotoxic [18].…”

Section: Introductionmentioning

confidence: 99%

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The novel phospholipid mimetic KPC34 is highly active against preclinical models of Philadelphia chromosome positive acute lymphoblastic leukemia

et al. 2017

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Philadelphia chromosome positive B cell acute lymphoblastic leukemia (Ph+ ALL) is an aggressive cancer of the bone marrow. The addition of tyrosine kinase inhibitors (TKIs) has improved outcomes but many patients still suffer relapse and novel therapeutic agents are needed. KPC34 is an orally available, novel phospholipid conjugate of gemcitabine, rationally designed to overcome multiple mechanisms of resistance, inhibit the classical and novel isoforms of protein kinase C, is able to cross the blood brain barrier and is orally bioavailable. KPC34 had an IC50 in the nanomolar range against multiple ALL cell lines tested but was lowest for Ph+ lines. In mice bearing either naïve or resistant Ph+ ALL, KPC34 treatment resulted in significantly improved survival compared to cytarabine and gemcitabine. Treatment with KPC34 and doxorubicin was more effective than doxorubicin and cytarabine. Mice with recurrence of their ALL after initial treatment with cytarabine and doxorubicin saw dramatic improvements in hind limb paralysis after treatment with KPC34 demonstrating activity against established CNS disease. Consistent with this KPC34 was better than gemcitabine at reducing CNS leukemic burden. These promising pre-clinical results justify the continued development of KPC34 for the treatment of Ph+ALL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The novel phospholipid mimetic KPC34 is highly active against preclinical models of Philadelphia chromosome positive acute lymphoblastic leukemia

et al. 2017

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“…In chronic phase, CML has slow disease onset and late occurrence of symptoms. After diagnosis, however, patients are mostly in the accelerating phase, thus increasing the difficulty of treatment [7]. Although significant improvements have been obtained, CML is inherently insensitive to chemotherapy and other classical approaches, thus impeding the improvement of 5-year survival rate [6].…”

Section: Discussionmentioning

confidence: 99%

“…Currently, targeted drugs for BCR/ABL fusion protein combined with tyrosine kinase inhibitors are major approaches for treating CML. Currently available tyrosine kinase inhibitors such as imatinib are only effective during the chronic phase, but have poor efficacy in BCR/ABL fusion protein-positive disease during the acute phase, and is ineffective for CML stem cells during the latent stage [6,7]. Other common chemotherapy agents such as hydroxyurea and myleran lack tumor specificity, thus causing poor efficacy in CML [8].…”

Section: Introductionmentioning

confidence: 99%

Induction of K562 Cell Apoptosis by As4S4 via Down-Regulating miR181

et al. 2017

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BackgroundChronic myelogenous leukemia (CML) has unsatisfactory treatment efficacy at present. As the major component of red orpiment, tetra-arsenic tetra-sulfide (As4S4) has been recently used in treating leukemia, but with unclear mechanism targeting CML. MicroRNA (miR) is a group of endogenous non-coding RNAs regulating pathogenesis. MiR181 has been shown to exert important roles in tumor progression. The relationship between miR181 and As4S4 in inducing K562 cell apoptosis, however, is still unclear.Material/MethodsCML cell line K562 was cultured in vitro in a control group and in groups receiving various dosages (20 μM and 40 μM) of As4S4. MTT assay was employed to detect the effect on K562 cell survival. MiR181 expression was quantified by real-time PCR. MTT assay and assay kit were used to determine K562 cell survival and caspase 3 expression. Cell apoptosis was assessed by flow cytometry. Bcl-2 expression was determined by real-time PCR and Western blotting.ResultsAs4S4 significantly suppressed proliferation of K562 cells (p<0.05) and decreased miR181 expression, and increased caspase3 activity compared to the control group. It can induce K562 cell apoptosis via remarkably down-regulating mRNA and protein expressions of Bcl-2 (p<0.05).ConclusionsAs4S4 can facilitate K562 cell apoptosis via down-regulating miR181, inhibiting Bcl02 expression, and enhancing apoptotic protein caspase3 activity.

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“…Tüm KML hastalarının yaklaşık %95'inde t(9;22)(q34;q11) translokasyonu görülür ve oluşan kimerik "Philadelphia" kromozomu BCR-ABL füzyon genini barındırır. Füzyon genin transkript ürünlerinden birisi olan p210BCR/ABL proteini bir tirozin kinazdır (1).…”

Section: Introductionunclassified

Genistein ve STI571’in (Imatinib) Kronik Myeloblastik Losemide Etkili Sinyal Protein Duzeylerine Etkileri

Armutçuoğlu¹,

Kasap²,

Yurtçu

2018

GMJ

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Inhibition of crosstalk between Bcr-Abl and PKC signaling by PEITC, augments imatinib sensitivity in chronic myelogenous leukemia cells

Cited by 17 publications

References 28 publications

The novel phospholipid mimetic KPC34 is highly active against preclinical models of Philadelphia chromosome positive acute lymphoblastic leukemia

The novel phospholipid mimetic KPC34 is highly active against preclinical models of Philadelphia chromosome positive acute lymphoblastic leukemia

Induction of K562 Cell Apoptosis by As4S4 via Down-Regulating miR181

Genistein ve STI571’in (Imatinib) Kronik Myeloblastik Losemide Etkili Sinyal Protein Duzeylerine Etkileri

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