Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101

Riyahi, Niknam; Safaroghli‐Azar, Ava; Sheikh-Zeineddini, Negar; Sayyadi, Mohammad; Bashash, Davood

doi:10.1080/07357907.2019.1651328

Cited by 10 publications

(4 citation statements)

References 43 publications

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“…Of note, we found that, upon the inhibition of PI3K, AT7519 was able to more vigorously diminish the survival and proliferative rate of K562, which may indicate the involvement of the PI3K axis in the mechanism of action of the inhibitor. In accordance with our finding, other studies have also announced the ability of PI3K inhibitors to potentiate the cytotoxic effect of several small molecule inhibitors in human leukemia (Bashash et al, 2019;Riyahi et al, 2019), indicative of the attenuating role of the PI3K pathway on the death signals induced by different anticancer drugs. Dolman et al (2015) indicated that AT7519 could exert a prominent anti-cancer effect in both MYCN-amplified neuroblastoma cell lines and AMC711T xenografts through reductions in the levels of phosphorylated retinoblastoma.…”

Section: Discussionsupporting

confidence: 92%

Anti-proliferative effects of a small molecule inhibitor of CDK AT7519 on chronic myeloid leukemia (CML) cells through halting the transition of cells from G2/M phase of the cell cycle

Oghabi¹,

Safaroghli‐Azar²,

Pourbagheri‐Sigaroodi³

et al. 2020

Biocell

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Pathogenesis of chronic myeloid leukemia (CML) has mostly been studied with regard to the oncogenic role of BCR/ABL fusion; however, recent disclosures have declared that the challenges with the treatment of CML patients would not be resolved until the role of other aberrancies is ignored. Given the involvement of cyclin-dependent kinases (CDKs) in the pathogenesis of CML, the present study aimed to investigate the effects of a multi-CDK inhibitor AT7519 on BCR/ABL-harboring CML-derived K562 cells. Our results showed that AT7519 effectively reduced the survival of K562 and induced its anti-proliferative effect through the induction of G2/M arrest due to elevated p21 and p27. The resulting data also revealed that either direct or indirect suppression of c-Myc using specific c-Myc inhibitor 10058-F4 and selective PI3K inhibitor CAL-101 resulted in a superior cytotoxicity, suggesting that the activation of PI3K pathway could attenuate antileukemic effects of the inhibitor, at least partly, through a c-Mycdependent mechanism. To the best of our knowledge, to date, no study has addressed the effect of autophagy on CML cell response to AT7519, and, herein, we proposed for the first time that the suppression of autophagy boosted AT7519 cytotoxicity against K562. Overall, we suggested that selective CDK inhibitor AT7519 exerted antileukemic effect against CML cells and propose a novel therapeutic application for the inhibitor either as a single agent or in combination with c-Myc and/or PI3K inhibitors.

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Section: Discussionsupporting

confidence: 92%

Anti-proliferative effects of a small molecule inhibitor of CDK AT7519 on chronic myeloid leukemia (CML) cells through halting the transition of cells from G2/M phase of the cell cycle

Oghabi¹,

Safaroghli‐Azar²,

Pourbagheri‐Sigaroodi³

et al. 2020

Biocell

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“…Interestingly, our results showed that upon c‐Myc inhibition using 10058‐F4, the apoptotic effect of BKM120 on K562 cells became more prominent as compared with single‐agent of BKM120; shedding light on the role of c‐Myc in determining the extent of cell sensitivity to PI3K inhibitors. In consistent, the results of our recent studies also reported that co‐targeting of PI3K with c‐Myc produced a more prominent anti‐cancer effect in acute myeloid leukemia (Riyahi et al, 2019), acute lymphoblastic leukemia (Sheikh‐Zeineddini et al, 2019), and multiple myeloma (Safaroghli‐Azar et al, 2019) cells.…”

Section: Discussionsupporting

confidence: 87%

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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“…It has been reported that the activation of autophagy affects cancer cells’ response to small molecule inhibitors of various oncogenic proteins such as PI3K (Shiri Heris et al, 2020) and c‐Myc (Riyahi et al, 2019). Besides, while some reports have shown that inhibition of HDAC results in significant cytotoxicity through upregulation of autophagy (Thomas et al, 2011), other studies reported suppressive effects of HDAC inhibitors on this system (Stankov et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Abrogation of histone deacetylases (HDACs) decreases survival of chronic myeloid leukemia cells: New insight into attenuating effects of the PI3K/c‐Myc axis on panobinostat cytotoxicity

Zehtabcheh

Yousefi

Salari

et al. 2021

Cell Biology International

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Although the identification of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of many cancer types including chronic myeloid leukemia (CML), still adjustment of neoplastic cells to cytotoxic effects of anticancer drugs is a serious challenge. In the area of drug resistance, epigenetic alterations are at the center of attention and the present study aimed to evaluate whether blockage of epigenetics mechanisms using a pan‐histone deacetylase (HDAC) inhibitor induces cell death in CML‐derived K562 cells. We found that the abrogation of HDACs using panobinostat resulted in a reduction in survival of the K562 cell line through p27‐mediated cell cycle arrest. Noteworthy, the results of the synergistic experiments revealed that HDAC suppression could be recruited as a way to potentiate cytotoxicity of Imatinib and to enhance the therapeutic efficacy of CML. Here, we proposed for the first time that the inhibitory effect of panobinostat was overshadowed, at least partially, through the aberrant activation of the phosphoinositide 3‐kinase (PI3K)/c‐Myc axis. Meanwhile, we found that upon blockage of autophagy and the proteasome pathway, as the main axis involved in the activation of autophagy, the anti‐leukemic property of the HDAC inhibitor was potentiated. Taken together, our study suggests the beneficial application of HDAC inhibition in the treatment strategies of CML; however, further in vivo studies are needed to determine the efficacy of this inhibitor, either as a single agent or in combination with small molecule inhibitors of PI3K and/or c‐Myc in this malignancy.

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Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101

Cited by 10 publications

References 43 publications

Anti-proliferative effects of a small molecule inhibitor of CDK AT7519 on chronic myeloid leukemia (CML) cells through halting the transition of cells from G2/M phase of the cell cycle

Anti-proliferative effects of a small molecule inhibitor of CDK AT7519 on chronic myeloid leukemia (CML) cells through halting the transition of cells from G2/M phase of the cell cycle

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

Abrogation of histone deacetylases (HDACs) decreases survival of chronic myeloid leukemia cells: New insight into attenuating effects of the PI3K/c‐Myc axis on panobinostat cytotoxicity

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