Inhibition of PI3K signaling pathway enhances the chemosensitivity of APL cells to ATO: Proposing novel therapeutic potential for BKM120

Bashash, Davood; Delshad, Mahda; Riyahi, Niknam; Safaroghli‐Azar, Ava; Pourbagheri‐Sigaroodi, Atieh; Momeny, Majid

doi:10.1016/j.ejphar.2018.10.007

Cited by 19 publications

(9 citation statements)

References 39 publications

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“…Additionally, this favorable anti‐leukemic effect was evident in the synergistic experiments, where we found that the inhibition of PI3K could potentiate the anti‐leukemic effect of imatinib in this cell line. Our results were in accordance with recent studies highlighting that the inhibition of the PI3K‐signaling alone or in combination with chemotherapeutic drugs induced significant anti‐leukemic activity in different hematologic malignant cells through induction of apoptotic cell death (Allegretti et al, 2015; Bashash et al, 2018).…”

Section: Discussionsupporting

confidence: 93%

Anti‐leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c‐Myc and autophagy on BKM120 cytotoxicity

Heris

Safaroghli‐Azar

Yousefi

et al. 2020

Cell Biology International

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The success in the identification of BCR/ABL tyrosine kinase role in the pathogenesis of chronic myeloid leukemia (CML) went as far as to find a path to cure this leukemia; however, compensatory activation of leukomogenic signals get across the message that the small molecule inhibitors of oncogenic pathways, along with tyrosine kinase inhibitors, might be a beneficial approach in CML treatment. The results of the present study showed that the abrogation of the phosphoinositide 3-kinase (PI3K) pathway using pan-PI3K inhibitor BKM120 exerted a cytotoxic effect against CML-derived K562 cells through both the induction of p21-mediated G2/M arrest and the stimulation of apoptosis. Notably, the apoptotic effect of the inhibitor was further confirmed by the molecular analysis showing that BKM120 significantly increased the expression of pro-apoptotic genes. To the best of our knowledge, the involvement of autophagy in resistance to BKM120 has not been yet described and our study suggests for the first time that the elevation of autophagy-related genes might serve as a compensatory pathway to cease the anti-leukemic effect of BKM120 in K562; since we found a reinforced anti-survival event when the cells were treated with BKM120 in combination with autophagy inhibitor. In conclusion, the results of the present study showed that the abrogation of PI3K using BKM120 might be a befitting approach in CML treatment, either as a single agent or in a combined-modal strategy; however, further evaluations including clinical trials and in vivo investigations are demanded to ascertain the safety and the efficacy of the inhibitor in treatment strategies.

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Section: Discussionsupporting

confidence: 93%

Anti‐leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c‐Myc and autophagy on BKM120 cytotoxicity

Heris

Safaroghli‐Azar

Yousefi

et al. 2020

Cell Biology International

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“…We found that BKM120 upregulated the mRNA expressions of both p21 and p27; however, we could find no significant alteration in c-Myc level ( Figure 3A). It has been reported that the unrestrained activation of c-Myc could be directly responsible for the lower sensitivity of malignant cells to PI3K inhibitors [15]. Accordingly, we found that the suppression of c-Myc using 10058-F4 not only reduced KG-1 cell survival ( Figure 3B) but also boosted the cytotoxic effects of either BKM120 or idelalisib when used in a combined-modality treatment ( Figure 3C).…”

Section: Stimulatory Effect Of C-myc Suppression On Bkm120-induced Cysupporting

confidence: 58%

PI3K abrogation using pan PI3K inhibitor BKM120 give rise to a weighty anti-cancer effect on AML-derived KG-1 cells by inducing apoptosis and G2/M arrest

Sadeghi

Esmaeili

Pourbagheri‐Sigaroodi

et al. 2020

Tjh

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Amaç: PI3K aşırı ifadesi ile kemoterapiye direnç kazanılması arasındaki ilişki insan kanserlerinin konvansiyonel tedavi stratejilerinde devrim yaratmak yolunda cazip bir hedef oluşturarak bu yolağa olan ilgiyi büyük ölçüde artırmıştır. Bu çalışmamızda pan-PI3K inhibitörü BKM120'nin akut myeloid lösemi (AML) kökenli KG-1 ve U937 hücreleri üzerine hücresel ve moleküler inhibitor etkisini araştırmayı amaçladık. Gereç ve Yöntemler: AML tedavisinde BKM120'nin etkisinin altında yatan moleküler mekanizmalar ve antitümör tesirini araştırmak için çeşitli yöntemler oluşturduk ve BKM120 idarubisin kombinasyonunun etkisini kontrol etmek için deneyler yaptık. Bulgular: PI3K inhibisyonunun hücre canlılığı ve metabolik aktiviteyi azalttığını ve hücrelerde konsantrasyona bağımlı olarak büyümeyi baskılayıcı etki gösterdiğini bulduk. Ayrıca, BKM120'nin antiproliferatif etkilerini p21 aracılı G2/M hücre döngüsünü durdurmak yoluyla gösterdiğini ileri sürdük. İnhibitörün moleküler özellikler üzerindeki etkisinin araştırılması sadece BKM120'nin antiapoptotik NF-κB'nin hedeflerinin ifadesini azalttığını değil, fakat aynı zamanda bortezomib kullanarak NF-κB baskılanmasının inhibitörün sitotoksisitesini belirgin artırdığını ortaya koyarak BKM120'nin antilösemik etkisinin en azından kısmen NF-κB yolağı modülasyonuyla olduğunu gösterdi. İlginç olarak, tek başına BKM120'nin c-Myc ifadesini anlamlı değiştiremediği, ancak BKM120'nin AML hücrelerinin sağkalım oranlarını azaltma kapasitesinin 10058-F4 aracılı c-Myc inhibisyonu ile artması lösemik hücrelerde c-Myc'nin PI3K inhibitörüne yanıta katkıda bulunduğunu düşündürmektedir.

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“…Following this, inactivation of PI3K/Akt signaling pathway leads to the increased expression level of p53 and apoptosis (Y. Li et al, 2009; Figure 3). Recently, it has been confirmed that PI3K/Akt inhibitors, such as BKM120, as a novel treatment strategy, increases the sensitivity of the APL cells to ATO (Bashash et al, 2018). In addition, ATO suppresses the activation of STAT1/3, NF‐ k B, phospho‐Akt, and phospho‐ERK as well as enhancing the activity of p‐PTEN (Kim et al, 2017).…”

Section: Apoptotic Effects Of Ato On Apl Cells and Other Leukemia Cellsmentioning

confidence: 98%

“…One of the mechanisms of ATO‐induced apoptosis in leukemia cells, is mediated by PI3K/Akt signaling pathway (Bashash et al, 2018; Q. Y. Chen & Costa, 2018; Y. Li et al, 2009). PI3K/Akt is one of the signaling pathways inhibiting apoptosis through an increase in the expression level of Mdm2, p53 inhibitor protein, as well as suppressing proapoptotic proteins (Mayer & Arteaga, 2016; Figure 3).…”

Section: Apoptotic Effects Of Ato On Apl Cells and Other Leukemia Cellsmentioning

confidence: 99%

Mechanistic effects of arsenic trioxide on acute promyelocytic leukemia and other types of leukemias

Yousefnia

2021

Cell Biology International

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Acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia characterized with a translocation between promyelocytic leukemia gene (PML) on chromosome 15 and retinoic acid receptor alpha gene (RARα) on chromosome 17. Transcription of this fusion gene results in PML/RARα fusion protein blocking expression of critical genes involved in differentiation of myeloid cells through interaction with RAR element. PML/RARα fusion protein prevents normal function of PML and RARα as well as inhibiting apoptosis. Arsenic trioxide (ATO) is an important agent for the treatment of relapsed and newly diagnosed APL. ATO induces apoptosis, autophagy, and partial cellular differentiation as well as inhibiting cell growth and angiogenesis. Recognition of signaling pathways and molecular mechanisms induced by ATO can be effective for discovering novel treatment strategies to target leukemia cells. Also, it can be developed for the treatment of a variety of cancer cells. This review provides a perspective on anticancerous effects of ATO on APL and leukemia cells.

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Inhibition of PI3K signaling pathway enhances the chemosensitivity of APL cells to ATO: Proposing novel therapeutic potential for BKM120

Cited by 19 publications

References 39 publications

Anti‐leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c‐Myc and autophagy on BKM120 cytotoxicity

Anti‐leukemic effect of PI3K inhibition on chronic myeloid leukemia (CML) cells: shedding new light on the mitigating effect of c‐Myc and autophagy on BKM120 cytotoxicity

PI3K abrogation using pan PI3K inhibitor BKM120 give rise to a weighty anti-cancer effect on AML-derived KG-1 cells by inducing apoptosis and G2/M arrest

Mechanistic effects of arsenic trioxide on acute promyelocytic leukemia and other types of leukemias

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