The PI3K signaling pathway; from normal lymphopoiesis to lymphoid malignancies.

INTRODUCTION: As a vital mechanism of survival, lymphopoiesis requires the collaboration of different signaling molecules to orchestrate each step of cell development and maturation. The PI3K pathway is considerably involved in the maturation of lymphatic cells and therefore, its dysregulation can immensely affect human well-being and cause some of the most prevalent malignancies. As a result, studies that investigate this pathway could pave the way for a better understanding of the lymphopoiesis mechanisms, the undesired changes that lead to cancer progression, and how to design drugs to solve this issue. AREAS COVERED: The present review addresses the aforementioned aspects of the PI3K pathway and helps pave the way for future therapeutic approaches. In order to access the articles, databases such as Medicine Medline/PubMed, Scopus, Google Scholar, and Science Direct were utilized. The search formula was established by identifying main keywords including PI3K/Akt/mTOR pathway, Lymphopoiesis, Lymphoid malignancies, and inhibitors. EXPERT OPINION: The PI3K pathway is crucial for lymphocyte development and differentiation, making it a potential target for therapeutic intervention in lymphoid cancers. Studies are focused on developing PI3K inhibitors to impede the progression of hematologic malignancies, highlighting the pathway's significance in lymphoma and lymphoid leukemia.

The PI3K/Akt signaling axis and type 2 diabetes mellitus (T2DM): From mechanistic insights into possible therapeutic targets.

Type 2 diabetes mellitus (T2DM) is an immensely debilitating chronic disease that progressively undermines the well-being of various bodily organs and, indeed, most patients succumb to the disease due to post-T2DM complications. Although there is evidence supporting the activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway by insulin, which is essential in regulating glucose metabolism and insulin resistance, the significance of this pathway in T2DM has only been explored in a few studies. The current review aims to unravel the mechanisms by which different classes of PI3Ks control the metabolism of glucose; and also to discuss the original data obtained from international research laboratories on this topic. We also summarized the role of the PI3K/Akt signaling axis in target tissues spanning from the skeletal muscle to the adipose tissue and liver. Furthermore, inquiries regarding the impact of disrupting this axis on insulin function and the development of insulin resistance have been addressed. We also provide a general overview of the association of impaired PI3K/Akt signaling pathways in the pathogenesis of the most prevalent diabetes-related complications. The last section provides a special focus on the therapeutic potential of this axis by outlining the latest advances in active compounds that alleviate diabetes via modulation of the PI3K/Akt pathway. Finally, we comment on the future research aspects in which the field of T2DM therapies using PI3K modulators might be developed.

Inhibition of PI3K/AKT signaling using BKM120 reduced the proliferation and migration potentials of colorectal cancer cells and enhanced cisplatin-induced cytotoxicity.

BACKGROUND: Although extensive efforts have been made to improve the treatment of colorectal cancer (CRC) patients, the prognosis for these patients remains poor. A wide range of anti-cancer agents has been applied to ameliorate the clinical management of CRC patients; however, drug resistance develops in nearly all patients. Based on the prominent role of PI3K/AKT signaling in the development of CRC and current interest in the application of PI3K inhibitors, we aimed to disclose the exact mechanism underlying the efficacy of BKM120, a well-known pan-class I PI3K inhibitor, in CRC-derived SW480 cells. MATERIALS AND METHODS: The effects of BKM120 on SW480 cells were studied using MTT assay, cell cycle assay, Annexin V/PI apoptosis tests, and scratch assay. In the next step, qRT-PCR was used to investigate the underlying molecular mechanisms by which the PI3K inhibitor could suppress the survival of SW480 cells. RESULT: The results of the MTT assay showed that BKM120 could decrease the metabolic activity of SW480 cells in a concentration and time-dependent manner. Investigating the exact mechanism of BKM120 showed that this PI3K inhibitor induces its anti-survival effects through a G2/M cell cycle arrest and apoptosis-mediated cell death. Moreover, the scratch assay demonstrated that PI3K inhibition led to the inhibition of cancer invasion and inhibition of PI3K/AKT signaling remarkably sensitized SW480 cells to Cisplatin. CONCLUSION: Based on our results, inhibition of PI3K/AKT signaling can be a promising approach, either as a single modality or in combination with Cisplatin. However, further clinical studies should be performed to improve our understanding.

C-Myc inhibition intensified the anti-leukemic properties of Imatinib in chronic myeloid leukemia cells.

BACKGROUND: Due to its remarkable efficacy in producing hematologic, cytogenetic, and molecular remissions, the FDA approved Imatinib as the first-line treatment for newly diagnosed Chronic Myeloid Leukemia (CML) patients. However, in some patients, failure to completely eradicate leukemic cells and the escape of these cells from death will lead to the development of resistance to Imatinib, and many are concerned about the prospects of this Tyrosine Kinase Inhibitor (TKI). It has been documented that the compensatory overexpression of c-Myc is among the most critical mechanisms that promote drug efflux and resistance in CML stem cells. METHODS: In order to examine the potential of c-Myc inhibition through the use of 10058-F4 to enhance the anti-leukemic properties of Imatinib, we conducted trypan blue and MTT assays. Additionally, we employed flow cytometric analysis and qRT-PCR to assess the effects of this combination on cell cycle progression and apoptosis. RESULTS: The findings of our study indicate that the combination of 10058-F4 and Imatinib exhibited significantly stronger anti-survival and anti-proliferative effects on CML-derived-K562 cells in comparison to either agent administered alone. It is noteworthy that these results were also validated in the CML-derived NALM-1 cell line. Molecular analysis of this synergistic effect revealed that the inhibition of c-Myc augmented the efficacy of Imatinib by modulating the expression of genes related to cell cycle, apoptosis, autophagy, and proteasome. CONCLUSIONS: Taken together, the findings of this investigation have demonstrated that the suppression of the c-Myc oncoprotein through the use of 10058-F4 has augmented the effectiveness of Imatinib, suggesting that this amalgamation could offer a fresh perspective on an adjunctive treatment for individuals with CML. Nevertheless, additional scrutiny, encompassing in-vivo examinations and clinical trials, is requisite.

Inhibition of PI3K Signaling Intensified the Antileukemic Effects of Pioglitazone: New Insight into the Application of PPARγ Stimulators in Acute Lymphoblastic Leukemia.

Over the past two decades, molecular targeted therapy has revolutionized the landscape of cancer treatment due to lower side effects as well as higher anticancer effects. Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the nuclear hormone receptor which plays a crucial role in cell proliferation and death and the efficacy of PPARγ ligands either as monotherapy or in combination with traditional chemotherapy drugs has been proved by recent studies. In this study, we aimed to investigate the effects of pioglitazone, a well-known PPARγ stimulator, in ALL-derived NALM6 cells by using trypan blue assay, MTT assay, and flow cytometry analysis. Moreover, to investigate the molecular mechanism action of pioglitazone in these cells, we assessed the possible alterations in the expression of some target genes which regulate cell proliferation, apoptosis, and autophagy system. Our result demonstrated that pioglitazone induced a remarkable antileukemic effect on NALM6 cells through a PTEN-mediated manner. Based on the fact that PI3K hyperactivation is one of the main properties of ALL cells, the effects of PI3K inhibition using CAL-101 on pioglitazone-induced cytotoxicity were evaluated by combinatorial experiments. Moreover, the result of cell cycle assay and qRT-PCR demonstrated that pioglitazone-CAL-101 induced antileukemic effect mainly through induction of p21 and p27-mediated G1 arrest. Additionally, our result showed that inhibition of proteasome and autophagy system, two main cellular processes, increased the antileukemic effects of the agents. Taken together, we suggest a novel therapeutic application for PPARγ stimulators as a single agent or in combination with PI3K inhibitors that should be clinically evaluated in ALL patients.

Cyclins and cyclin-dependent kinases: from biology to tumorigenesis and therapeutic opportunities.

The discussion on cell proliferation cannot be continued without taking a look at the cell cycle regulatory machinery. Cyclin-dependent kinases (CDKs), cyclins, and CDK inhibitors (CKIs) are valuable members of this system and their equilibrium guarantees the proper progression of the cell cycle. As expected, any dysregulation in the expression or function of these components can provide a platform for excessive cell proliferation leading to tumorigenesis. The high frequency of CDK abnormalities in human cancers, together with their druggable structure has raised the possibility that perhaps designing a series of inhibitors targeting CDKs might be advantageous for restricting the survival of tumor cells; however, their application has faced a serious concern, since these groups of serine-threonine kinases possess non-canonical functions as well. In the present review, we aimed to take a look at the biology of CDKs and then magnify their contribution to tumorigenesis. Then, by arguing the bright and dark aspects of CDK inhibition in the treatment of human cancers, we intend to reach a consensus on the application of these inhibitors in clinical settings.

Synergistic effects of PI3K inhibition and pioglitazone against acute promyelocytic leukemia cells.

BACKGROUND: Although pioglitazone, a well-known anti-diabetic agent, has recently established itself as a pillar of cancer treatment, its therapeutic value could be attenuated by the aberrant activation of the PI3K/Akt pathway. AIM: To evaluate whether the PI3K/Akt suppression in leukemic cells could potentiate the anti-leukemic effects of pioglitazone. METHODS: To assess the anti-leukemic effects of PI3K/Akt inhibitors on anti-leukemic effects of pioglitazone, we used MTT and trypan blue assays. Flow cytometric analysis and qRT-PCR were also applied to evaluate cell cycle and apoptosis. RESULT: The resulting data revealed that upon PPARγ stimulation in different leukemic cell lines using pioglitazone, the survival and the proliferative capacity of the cells were significantly halted. Then, we evaluated the impact of the PI3K/Akt axis on the effectiveness of the drug in the most sensitive leukemic cell line; NB4 cells. Our results showed that treatment of NB4 cells with the PI3K inhibitors increased the sensitivity of leukemic cells to pioglitazone to the degree that even lower concentrations of the agent succeeded to induce apoptotic as well as the anti-proliferative effects. Moreover, it seems that PI3K inhibition could potentiate the anti-leukemic effect of pioglitazone through induction of p21-mediated sub-G1 cell cycle arrest and altering the balance between the pro-and anti-apoptotic genes. CONCLUSION: This study sheds light on the significance of the PI3K/Akt pathway in APL cell sensitivity to pioglitazone and proposed that the presence of the PI3K inhibitor in the therapeutic regimen containing pioglitazone could be promising in the treatment of this malignancy.

The DNA Methylation in Neurological Diseases.

DNA methylation is critical for the normal development and functioning of the human brain, such as the proliferation and differentiation of neural stem cells, synaptic plasticity, neuronal reparation, learning, and memory. Despite the physical stability of DNA and methylated DNA compared to other epigenetic modifications, some DNA methylation-based biomarkers have translated into clinical practice. Increasing reports indicate a strong association between DNA methylation profiles and various clinical outcomes in neurological diseases, making DNA methylation profiles valuable as novel clinical markers. In this review, we aim to discuss the latest evidence concerning DNA methylation alterations in the development of neurodegenerative, neurodevelopmental, and neuropsychiatric diseases. We also highlighted the relationship of DNA methylation alterations with the disease progression and outcome in many neurological diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and autism.

An overview of long noncoding RNAs: Biology, functions, therapeutics, analysis methods, and bioinformatics tools.

Long noncoding RNAs (lncRNAs) are a diverse class of RNAs whose functions are widespread in all branches of life and have been the focus of attention in the last decade. While a huge number of lncRNAs have been identified, there is still much work to be done and plenty to be learned. In the current review, we begin with the biogenesis and function of lncRNAs as they are involved in the different cellular processes from regulating the architecture of chromosomes to controlling translation and post-translation modifications. Questions on how overexpression, mutations, or deficiency of lncRNAs can affect the cellular status and result in the pathogenesis of various human diseases are responded to. Besides, we allocate an overview of several studies, concerning the application of lncRNAs either as diagnostic and prognostic biomarkers or novel therapeutics. We also introduce the currently available techniques to explore details of lncRNAs such as their function, cellular localization, and structure. In the last section, as exponentially growing data in this area need to be gathered and organized in comprehensive databases, we have a particular focus on presenting general and specialized databases. Taken together, with this review, we aim to provide the latest information on different aspects of lncRNAs to highlight their importance in physiopathologic states and take a step towards helping future studies.

CAR NK cell therapy in hematologic malignancies and solid tumors; obstacles and strategies to overcome the challenges.

Adoptive cell treatment (ACT) utilizing chimeric antigen receptors (CAR) diverts the specificity of safe cells against a target-specific antigen and portrays exceptional potential for cancer treatment. While CAR T cell treatment has risen as a breakthrough with unprecedented results within the therapeutic procedures of human malignancies, different deficiencies including challenging and costly generation processes, strict patient qualification criteria, and undesirable toxicity have ruined its application. Unlike T cells, the application of natural killer (NK) cells has attracted consideration as a reasonable alternative owing to the major histocompatibility complex (MHC)-independency, shorter life expectancy, the potential to create an off-the-shelf immune product, and potent antitumor properties. In this article, we provide an updated review of the differences between CAR T and CAR NK cells, current enhancements in CAR NK design, the available sources for collecting NK cells, and strategies for the transduction step of the CARs to NK cells. Furthermore, we focus on the published and ongoing preclinical and clinical studies of CAR NK treatment strategies both in hematologic malignancies and solid tumors. We also discuss limitations and plausible solutions to improve the perseverance, function, safety, and efficacy of CAR NK cells with a special focus on solid tumors.

Noncoding RNAs in diagnosis and prognosis of graft-versus-host disease (GVHD).

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a functional therapy for a plethora of hematologic malignancies and immune disorders. Graft-versus-host disease (GVHD), on the other hand, is one of the major complications ahead of a successful HSCT, contributing to transplant-associated morbidity and mortality. Notably, little is known about the underlying mechanism of this event; therefore, exploring precise biomarkers and uncovering the molecular pathogenesis of GVHD is valuable for early diagnosis and treatment optimization. Thanks to the advances in sequencing techniques, the noncoding sequences of the human genome-formerly considered "junk"-are now identified as functional molecules. Noncoding RNAs (ncRNA) control cellular responses by regulating gene expression, and previous studies have shown that these tiny molecules, especially microRNAs (miRNAs), can affect allogeneic T cell responses in both animal models and clinical experiments. The present study gives an overview of the functions of various miRNAs in regulating T cell responses in GVHD. We also provide an outlook on miRNAs and long noncoding RNAs (lncRNAs) potential role in GVHD with the hope of providing a future research direction for expanding their application as the sensitive and noninvasive diagnostic or prognostic biomarkers and also the promising therapeutic targets for improving outcomes after allogeneic HSCT.

The Superior Cytotoxicity of Dual Targeting of BCR/ABL and PI3K in K562 Cells: Proposing a Novel Therapeutic Potential for the Treatment of CML.

Apart from BCR/ABL which is the main player in the pathogenesis of chronic myeloid leukemia (CML), the role of other signaling cascades should not be underestimated especially for the maintenance of leukemic cells survival. The results of the present study indicate that either an isoform-specific or a pan-PI3K inhibitor could potently reduce the survival of CML-derived K562 cells, shedding more light on the involvement of the PI3K axis in the pathogenesis of CML. Of particular interest, the importance of the PI3K pathway in this disease became more evident when we found that there was a more remarkable reduction in the viability of K562 cells when BKM120 was used in combination with imatinib. Moreover, BKM120 robustly enhanced the growth-suppressive effect of imatinib through p21-mediated induction of G2/M cell cycle arrest and induction of apoptotic cell death. Despite the favorable anti-survival effects of the drug combination, these agents failed to induce inhibitory effects on the expression of c-Myc and NF-κB anti-apoptotic target genes. However, the ability of combinational therapy in diminishing K562 cell survival was potentiated either in the presence of 10058-F4 (c-Myc inhibitor) or Bortezomib (proteasome inhibitor), suggestive of the role of both NF-κB and c-Myc in overshadowing the therapeutic value of drugs combination. Taken together, the results of this study showed that inhibition of the PI3K pathway is a suitable approach to enhance the therapeutic value of imatinib in the treatment of CML.

Anticancer Effects of ZnO/CNT@Fe3O4 in AML-Derived KG1 Cells: Shedding Light on Promising Potential of Metal Nanoparticles in Acute Leukemia.

Background: Therapeutic approaches for acute myeloid leukemia (AML) have remained largely unchanged for over 40 years and cytarabine and an anthracycline (e.g., daunorubicin) backbone is the main induction therapy for these patients. Resistance to chemotherapy is the major clinical challenge and contributes to short-term survival with a high rate of disease recurrence. Given the established efficacy of nanoparticles in cancer treatment, this study was designed to evaluate the anticancer property of our novel nanocomposite in the AML-derived KG1 cells. Materials and Methods: To assess the anti-leukemic effects of our nanocomposite on AML cells, we used MTT and trypan blue assays. Flow cytometric analysis and q-RT-PCR were also applied to evaluate the impact of nanocomposite on cell cycle and apoptosis. Results: Our results outlined that ZnO/CNT@Fe3O4 decreased viability and metabolic activity of KG1 cells through induction of G1 arrest by increasing the expression of p21 and p27 cyclin-dependent kinase inhibitors and decreasing c-Myc transcription. Moreover, ZnO/CNT@Fe3O4 markedly elevated the percentage of apoptotic cells which was coupled with a significant alteration of Bax and Bcl-2 expressions. Synergistic experiments showed that ZnO/CNT@Fe3O4 enhances the cytotoxic effects of Vincristine on KG1 cells. Conclusion: In conclusion, this study sheds light on the potent anti-leukemic effects of ZnO/CNT@Fe3O4 and provides evidence for the application of this agent in the treatment of acute myeloid leukemia.

Predictive value of PD-L1 expression in response to immune checkpoint inhibitors for esophageal cancer treatment: A systematic review and meta-analysis.

Background: Programmed death-ligand-1 (PD-L1) molecule is a well-known predictive biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in several cancers. Present systematic review and meta-analysis aimed at investigating the role of PD-L1 in predicting the effectiveness of programmed death-1 (PD-1)/PD-L1 inhibitors in patients suffering from esophageal cancer. Methods: We searched PubMed, Scopus, Web of Science, and EMBASE databases as of March 25, 2022, for retrieving the potential relevant randomized controlled trials (RCTs). The pooled hazard ratios (HR) and the corresponding 95% confidence intervals (95%CIs) were calculated for the outcomes of overall survival (OS) and progression-free survival (PFS). The primary objective was to investigate the association between PD-1/PD-L1 inhibitors vs. control agents and treatment efficacy in terms of OS in patients with esophageal tumor expressing different values of PD-L1 based on combined-positive score (CPS) and tumor proportion score (TPS). The secondary outcome was the pooled risk of PFS. Results: Eleven studies with a total of 5,418 participants were included. While there was no difference in the OS of CPS<1 patients in the intervention and the control group, patients bearing esophageal tumors with a CPS≥1 (HR 0.65, 0.56-0.74) treated by ICIs showed a significant improvement in OS relative to the control agents. Accordingly, patients with CPS<5 (HR 0.75, 0.58-0.98), CPS≥5 (HR 0.64, 0.53-0.77), CPS<10 (HR 0.86, 0.76-0.98), and CPS≥10 (HR 0.65, 0.56-0.75) had improved OS; however, a significant longer OS was observed in cases who expressed higher values of CPS=10 (p=0.018). In terms of TPS, a significant greater benefit in prolonging the OS came from TPS≥1% PD-L1 expressing tumors in comparison to TPS<1% tumors, suggesting this cut-off as another predictor of PD-1/PD-L1 inhibitors efficacy. Notably, in the subgroup analysis when the cut-off value of CPS=10 or TPS=1% was selected, Nivolumab was the best ICI that improved the survival of PD-L1 positive patients. In patients with negative PD-L1 expression, Toripalimib is the only ICI which could prolong the OS of patients with the cut-off value of CPS=10. Conclusion: Among patients suffering from esophageal cancer, PD-L1 CPS=10 and TPS=1% expression thresholds seem to be predictive of a lower rate of mortality when PD-1/PD-L1 inhibitors are administrated; however, further large-scale trials are required for confirming the findings of the present study.

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.

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.

Suppression of proteasome induces apoptosis in APL cells and increases chemo-sensitivity to arsenic trioxide: Proposing a perception in APL treatment.

In the last three decades, the pathogenesis of acute promyelocytic leukemia (APL) has been mostly studied with regard to the oncogenic role of PML/RAR fusion protein; however, the latest discoveries have stated that the concerns with the treatment of APL patients would not be resolved until the role of aberrant networks is overlooked. The present study was designed to evaluate the anti-cancer property of second-generation of the proteasome inhibitors carfilzomib (CFZ) on APL-derived NB4 cells. Our results showed that pharmacologic targeting of proteasome in NB4 reduced the proliferative rate of malignant cells through a c-Myc-mediated G2/M cell cycle arrest. Moreover, we found that the suppression of proteasome was coupled with the induction of apoptotic NB4 cell death, which is probably mediated through down-regulation of anti-apoptotic target genes. Interestingly, our results suggested that the suppression of the autophagy system using chloroquine could serve as a mechanism through which the cytotoxicity of CFZ in APL cells was ameliorated. Finally, and consistent with the favorable efficacy of single agent of CFZ, we also noted an intensifying effect of the inhibitor on the anti-leukemic activity of arsenic trioxide (ATO) when it was used in combination. Overall, this study suggests that pharmaceutical targeting of proteasome using CFZ, either as a single agent or in combination with ATO, could be a promising mechanism through which the obstacle on the way of APL would be tackled; however, further investigations are needed to determine the advantages of the inhibitor in clinical applications.

Application of ZnO/CNT@Fe3O4nanocomposite in amplifying the anti-leukemic effects of Imatinib: a novel strategy to adjuvant therapy in chronic myeloid leukemia.

The advent of tyrosine kinase inhibitors in the therapeutic protocols of chronic myeloid leukemia (CML) was a revolution in the treatment strategies that guaranteed the achievement of complete remission for patients. However, due to different mutations bypassing the efficacy of Imatinib, novel and more effective treatments are indeed required for the treatment of CML. Our study declared that the combination of synthesized ZnO/CNT@Fe3O4nanocomposite with Imatinib decreased survival of CML-derived K562 cells, probably through inducing reactive oxygen species-mediated apoptosis. We also found improved cytotoxicity in the presence of a well known autophagy inhibitor, indicating that the apoptotic effect of this treatment is enhanced via autophagy suppression. Investigating the molecular mechanisms for the growth-suppressive effect of ZnO/CNT@Fe3O4-plus-Imatinib suggested that up-regulation of SIRT1 ceased cell cycle progression by increasing the expression of p21 and p27 cyclin-dependent kinase inhibitors. Notably, we reported here for the first time that either direct or indirect suppression of c-Myc results in enhanced anti-leukemic efficacy, suggesting that overexpression of c-Myc plays a contributory role in attenuating the efficacy of ZnO/CNT@Fe3O4-Imatinib in K562 cells. Given the promising effect of ZnO/CNT@Fe3O4in potentiating the anti-cancer effects of Imatinib in K562 cells, our study suggested that nanocomposite could be used as a tool for combined-strategy treatment. However, furtherin vivoexperiments are needed to provide clues for the safety and efficacy of this nanocomposite.

ZnO/CNT@Fe3O4 induces ROS-mediated apoptosis in chronic myeloid leukemia (CML) cells: an emerging prospective for nanoparticles in leukemia treatment.

The advent of nanoparticles revolutionised the drug delivery systems in human diseases; however, their prominent role was highlighted in the cancer-based therapies, where this technology could specifically target cancer cells. Herein, we decided to combine two nanoparticles Fe3O4 and ZnO to fabricate a new anti-cancer nanocomposite. Noteworthy, hydroxylated carbon nanotube (CNT) was used to increase the water-solubility of the compound, improving its uptake by malignant cells. This study was designed to evaluate the anticancer property as well as the molecular mechanisms of ZnO/CNT@Fe3O4 nanocomposite cytotoxicity in CML-derived K562 cells. Our results outlined that ZnO/CNT@Fe3O4 decreased the proliferative capacity of K562 cells through induction of G1 arrest and induced apoptosis probably via ROS-dependent upregulation of FOXO3a and SIRT1. The results of qRT-PCR analysis also demonstrated that while ZnO/CNT@Fe3O4 significantly increased the expression of pro-apoptotic genes in K562 cells, it had no significant inhibitory effect on the expression levels of anti-apoptotic target genes of NF-κB; proposing an attenuating role of NF-κB signalling pathway in K562 cell response to ZnO/CNT@Fe3O4. Synergistic experiment showed that ZnO/CNT@Fe3O4 could enhance the cytotoxic effects of imatinib on K562 cells. Overall, it seems that pharmaceutical application of nanocomposites possesses novel promising potential for leukaemia treatment strategies.

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.

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.

Inhibition of Cyclin-dependent Kinase (CDK) Decreased Survival of NB4 Leukemic Cells: Proposing a p53-Independent Sensitivity of Leukemic Cells to Multi-CDKs Inhibitor AT7519.

An unbounded number of events exist beneath the intricacy of each particular hematologic malignancy, prompting the tumor cells into an unrestrained proliferation and invasion. Aberrant expression of cyclin-dependent kinases (CDKs) is one of these events which disrupts the regulation of cell cycle and subsequently, results in cancer progression. In this study, we surveyed the repressive impact of multi-CDK inhibitor AT7519 on a panel of leukemia-derived cell lines. Our data underlined that AT7519 abated the survival of all tested cells; however, in an overview, the response rate of leukemic cells to the inhibitor was varied irrespective of p53 status. Notably, the less sensitivity of leukemia cells to AT7519 was found to be mediated partly by the compensatory activation of c-Myc oncogene which was confirmed by the induction of a superior cytotoxicity upon its suppression in less sensitive cell. The blockage of cell cycle, as announced by induction of sub-G1 arrest as well as reduced S phase, resulted in a significant decrease in survival of acute promyelocytic leukemia (APL)-derived NB4 cells, as the most sensitive cell line, either as monotherapy or in combination with arsenic trioxide. Anti-leukemic effects of the inhibitor were further verified by apoptosis analysis, where we discovered that AT7519 induced apoptosis via alteration of pro- and anti-apoptotic genes in NB4. All in all, this study proposed that AT7519 is a rewarding agent opposed to APL; however, additional examinations should be performed to determine the advantages of this inhibitor in clinical setting.