Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells.

Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles' heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.

Blockade of JAK2/STAT3 intensifies the anti-tumor activity of arsenic trioxide in acute myeloid leukemia cells: Novel synergistic mechanism via the mediation of reactive oxygen species.

Reactive oxygen species (ROS) are essential mediators of crucial cellular processes including apoptosis, proliferation, survival and cell cycle. Their regulatory role in cancer progression has seen in different human malignancies such as acute myeloid leukemia (AML). AML patients suffer from high resistance of the tumors against routine therapeutics including ATO. ATO enhance reactive oxygen species levels and induce apoptosis and suppresses proliferation in AML cells. However, some pathways such as JAK2/STAT3 ease anti-tumor activity of ATO by reducing reactive oxygen species amount and protecting the cell from apoptosis. In the present study, we use ruxolitinib (potent JAK2 inhibitor) to increase the sensitivity of AML cells to ATO treatment. We test, the effect of this combination on metabolic activity, proliferation, colony formation, cell cycle distribution, apoptosis, oxidative stress and DNA damage. Our results showed that combination of ATO with ruxolitinib synergistically reduced metabolic activity, proliferation and survival of AML cell lines. This combination induced G1/S cell cycle arrest because of reactive oxygen species elevation and GSH reduction. Besides, enhancement of reactive oxygen species increased apoptosis rate in combination samples. We uncovered that the synergistic anti-tumor effect of ATO and ruxolitinib in AML cells mediates via reactive oxygen species elevation and DNA damage. Overall, our results show that the combinatorial therapy of AML cells is more effective than solo-targeted therapy.

The Potential Contribution of microRNAs in Anti-cancer Effects of Aurora Kinase Inhibitor (AZD1152-HQPA).

Neuroblastoma (NB) remains the critical challenge in pediatric oncology. It has the highest rate of spontaneous regression among all human cancers. Aurora kinase B (AURKB), a crucial regulator of malignant mitosis, is involved in chromosome segregation and cytokinesis. AZD1152-HQPA (Barasertib) is a small selective inhibitor of AURKB activity and currently bears clinical assessment for several malignancies. Studies suggested that microRNAs are involved in the pathobiology and chemoresistance of neuroblastoma. In the present study, we first investigated the restrictive potentials of AZD1152-HQPA on cell viability, colony formation, nucleus morphology, polyploidy, and cell-cycle distribution. We then studied the expressions level of 88 cancer-related miRNAs in untreated and AZD1152-HQPA-treated NB cell line (SK-N-MC) by real-time PCR using miRNA cancer-array system. After normalizing, the fold change of miRNAs was calculated in the AZD1152-HQPA-treated cell as compared to untreated. Our results demonstrate that the inhibition of AURKB by AZD1152-HQPA induced potent antitumor activity, suppressed cell survival, and triggered apoptosis and polyploidy in NB cells. AZD1152-HQPA, at a relevant concentration, modulated a substantial number of cancer-related miRNAs in NB cell. Interestingly, by screening the literature, among the 7 top AZD1152-HQPA-induced upregulated miRNAs (> 3-fold change; P < 0.01), all were potential tumor suppressors associated with cell apoptosis and cycle arrest, as well as inhibition of angiogenesis, invasion, and metastasis, while two downregulated miRNAs were known to have oncogenic function. Taken together, our study showed for the first time the potential contribution of miRNAs in the anti-cancer effects of AZD1152-HQPA.

Targeting of EGFR increase anti-cancer effects of arsenic trioxide: Promising treatment for glioblastoma multiform.

Glioblastoma multiform (GBM) accounts for the most common form of primary brain tumors with very limited survival rate. Drug resistance is the main challenges for good prognosis of GBM patients. Arsenic trioxide (ATO) as a multifunctional drug has been investigated for the treatment of several solid tumors. Amplification/overexpression of the epidermal growth factor receptor (EGFR) gene as a signature genetic abnormality of GBM tumors can be a chemoresistance mechanism. In this study, we use erlotinib as an EGFR inhibitor to increase the sensitivity of GBM cell lines to ATO treatment. We evaluate the effects of this combination on metabolic activity, viability, cell proliferation, colony formation, cell cycle distribution, migration, oxidative stress and reactive oxygen species production. Our results showed that combination of ATO with erlotinib synergistically reduced metabolic activity, proliferation and colony forming potential in treated GBM cell lines. This combination induced G2/M cell cycle arrest. We also found that wound-healing rate were suppressed only after combination treatment. In addition, apoptotic cell death and reactive oxygen species content significantly increased after combination treatment. The combination of ATO and erlotinib considerably interfere with survival and migration of treated GBM cell lines through cell cycle arrest and reactive oxygen species production. Present study uncovered that EGFR inhibition could overcome the resistance of glioblastoma cells to ATO treatment.

Reactive oxygen species generation and increase in mitochondrial copy number: new insight into the potential mechanism of cytotoxicity induced by aurora kinase inhibitor, AZD1152-HQPA.

Aurora-B kinase overexpression plays important roles in the malignant progression of prostate cancer (PCa). AZD1152-HQPA, as an inhibitor of Aurora-B, has recently emerged as a promising agent for cancer treatment. In this study, we aimed to investigate the effects of AZD1152-HQPA on reactive oxygen species (ROS) generation and mitochondrial function in PCa. We used AZD1152-HQPA (Barasertib), a highly potent and selective inhibitor of Aurora-B kinase. The effects of AZD1152-HQPA on cell viability, DNA content, cell morphology, and ROS production were studied in the androgen-independent PC-3 PCa cell line. Moreover, the mitochondrial copy number and the expression of genes involved in cell survival and cancer stem cell maintenance were investigated. We found that AZD1152-HQPA treatment induced defective cell survival, polyploidy, micronuclei formation, cell enlargement, and cell death by significant overexpression of p73, p21 and downregulation of cell cycle-regulatory genes in a drug concentration-dependent manner. Moreover, AZD1152 treatment led to an excessive ROS generation and an increase in the mitochondrial copy number not only in PC-3 but also in several other malignant cells. AZD1152 treatment also led to downregulation of genes involved in the maintenance of cancer stem cells. Our results showed a functional relationship between the aurora kinase inhibition, an increase in mitochondrial copy number, and ROS generation in therapeutic modalities of cancer. This study suggests that the excessive ROS generation may be a novel mechanism of cytotoxicity induced by the aurora kinase inhibitor, AZD1152-HQPA.