Antiproliferative Effect of Gaillardin from Inula oculus-christi in Human Leukemic Cells.

Gaillardin (GLN) is a sesquiterpene lactone isolated from the chloroform extract of Inula oculus-christi L. This natural compound has shown cytotoxicity in various cancerous cell line. However, its effect on leukemic cells is ambiguous. Due to the neurotoxicity of vincristine (VCR) in acute lymphoblastic leukemia (ALL), we aimed to examine the cytotoxic effects of GLN alone and in combination with vincristine on induction of apoptosis, and cell cycle progression in ALL cell lines (NALM-6 and MOLT-4). Our results displayed that GLN could induce cytotoxic effects in MOLT-4 and NALM-6 with IC50 values of 7.3 and 6.1 µM, respectively. In this study, we demonstrated that GLN induces cytotoxicity through G0/G1 phase arrest followed by apoptosis in a dose-dependent manner. Fortunately, this natural compound did not show significant cytotoxic effects on normal cells. This study demonstrated that GLN was capable to extend chemotherapeutic sensitivity in ALL cells by reducing VCR concentration without constraining its effectiveness. Therefore, it might act as a promising anticancer agent for the treatment of leukemia.

Status of blood transfusion in World Health Organization-Eastern Mediterranean Region (WHO-EMR): Successes and challenges.

BACKGROUND: Blood products are used for patient treatment and survival in the cases of major surgery, hematological disorders or cancer therapy. Presently the main blood components are not yet replaceable by artificial products and all activities related to blood transfusion is highly dependent on the healthcare development of each country. The World Health Organization Eastern Mediterranean Region (WHO-EMR) comprises of 21 member states with variable socio-economic status effective on blood transfusion activities. The fundamental motivation behind this research was to accumulate some data of blood practices in this region and to have an appropriate image of the WHO-EMR region. MATERIAL AND METHODS: The data were collected through the published papers or data, blood transfusion services websites, and the other health official websites like WHO. RESULTS: Among WHO-EMR countries there are some with a nationally organized blood transfusion establishment such as Egypt, Iran, Iraq, Kuwait, Morocco, Oman, Pakistan, and Syria. In a few, blood transfusion administrations are hospital-based like Saudi Arabia. The others are run by Red Crescent such as Bahrain, Tunisia and UEA or by Red Cross like Lebanon. Only Iran and UAE succeed to have 100% voluntary non-remunerated blood donors; however, most of them are still under the weight of family/replacement blood donation such as Afghanistan, Egypt, Iraq, Lebanon, Morocco, Saudi Arabia and Sudan or even paid donors like Pakistan and Yemen. The haemovigilance and training programs have been implemented in some countries including Bahrain, Iran, Jordan, Kuwait, Oman, Qatar, Saudi Arabia, Tunisia and UAE. Unfortunately, there are rare and inaccessible information about some EMR states like Djibouti, Palestine and Somalia so that little data can be independently discovered. CONCLUSION: In these countries different measures ought to be additionally designated to ensure blood products adequacy and safety such as the development of well-coordinated national blood transfusion centers with the increased government commitment, the establishment of a well-organized system for voluntary non-remunerated blood donor recruitment, the establishment of well-equipped laboratories for screening donor samples for transfusion transmitted infections (TTIs) for at least mandatory tests recommended by WHO, the implementation of an educational/training program for professionals working in the blood transfusion establishments or hospitals, the regular audit on the quality and the integrity of the blood transfusion chain, and the development of a regional network of collaboration to bolster the neighboring nations in the EMR through effective communication tools.

Electromagnetic radiation: a new charming actor in hematopoiesis?

INTRODUCTION: Electromagnetic waves play indispensable roles in life. Many studies addressed the outcomes of Electromagnetic field (EMF) on various biological functions such as cell proliferation, gene expression, epigenetic alterations, genotoxic, and carcinogenic effects, and its therapeutic applications in medicine. The impact of EMF on bone marrow (BM) is of high importance; however, EMF effects on BM hematopoiesis are not well understood. AREAS COVERED: Publications in English were searched in ISI Web of Knowledge and Google Scholar with no restriction on publication date. A literature review has been conducted on the consequences of EMF exposure on BM non-hematopoietic stem cells, mesenchymal stem cells, and the application of these waves in regenerative medicine. Human blood cells such as lymphocytes, red blood cells and their precursors are altered qualitatively and quantitatively following electromagnetic radiation. Therefore, studying the impact of EMF on related signaling pathways in hematopoiesis and hematopoietic stem cell (HSC) differentiation could give a better insight into its efficacy on hematopoiesis and its potential therapeutic usage. EXPERT OPINION: In this review, authors evaluated the possible biologic consequences of EMF on the hematopoiesis process in addition to its probable application in the treatment of hematologic disorders.

Ergolide, a potent sesquiterpene lactone induces cell cycle arrest along with ROS-dependent apoptosis and potentiates vincristine cytotoxicity in ALL cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: Inula oculus christi belongs to the family of Asteraceae and it was traditionally wide used in treatment of kidney stones and urethra infection; besides, recently the potent sesquiterpene lactones isolated from inula species has gained increasing attention in cancer treatments. This study investigates the anti-cancer properties and underlying mechanism of ergolide isolated from Inula oculus christi against leukemic cell lines. METHODS: Viability, metabolic activity and proliferation evaluated using different index of MTT assay such as IC50 and GI50. Human erythrocytes were used to evaluate hemolytic activity. Flow-cytometry was used to detect and measure ROS level, and the induction of apoptosis and autophagy were evaluated using Annexin V/PI, Acridine Orange staining, respectively. Moreover, qRT-PCR was performed to examine the expression of a large cohort of crucial regulatory genes. Tunel assay was also carried out to assess morphologically ergolide effects. RESULTS: Ergolide did not exert ant cytotoxicity against non-tumorous cells and did not cause noticeable hemolysis. It also caused ROS production during early hours after treatment of cells which was then followed by cell cycle arrest in G0/G1 phase and autophagy induction. Using N-acetyl-L-cysteine (NAC), we found that ergolide could not increase ROS and induce autophagy and moreover repressed cell death, indicating that ergolide induce cell death through ROS-dependent manner by altering the expression of pro apoptotic related genes. Autophagy inhibition also potentiated ergolide-induced cell death. Furthermore, ergolide intensified vincristine cytotoxicity against acute lymphoblastic leukemia (ALL) cell lines revealed robust synergistic properties of ergolide with VCR. CONCLUSION: Here we showed that ergolide could be considered as a potent natural compound against leukemic cells by inducing cell cycle arrest followed by dose-dependent cell death. Based on results, Autophagy response in a result of ROS accumulation acted as a survival pathway and blocking this pathway could noticeably increase ergolide cytotoxicity on ALL cell lines.

Methanolic Extract from Aerial Parts of Artemisia Annua L. Induces Cytotoxicity and Enhances Vincristine-Induced Anticancer Effect in Pre-B Acute Lymphoblastic Leukemia Cells.

Background: Nowadays, remarkable attention has been drawn towards the effective therapeutic characteristic of natural products targeting cancerous cells. This study aimed to investigate the anti-cancer effect of Artemisia annua extract (AAE), a Chinese herbal medicine alone and in combination with a microtubule binding agent used in ALL treatment, vincristine (VCR), in B-Acute lymphoblastic leukemia (ALL) Nalm-6 and Reh cells. Materials and Methods: Cytotoxic activity of AAE and VCR was determined using MTT assay in Nalm-6, and Reh cell lines and synergism was evaluated using the CompuSyn software. Caspase 3 activity and Annexin/PI staining were performed for apoptosis assessment. The expression level of apoptosis-related genes, caspase 3, Bax and Bcl-2 were determined using real time-PCR. One-way ANOVA and post hoc Tukey multiple comparisons were used for statistical analysis. Results: Our findings revealed that a single administration of AAE exerted an anti-leukemic effect in both ALL-derived cells in a time- and dose-dependent manner. Interestingly, the growth inhibitory activity of the extract was more potentiated when combined with 0.1 and 1 nM VCR through caspase 3-dependent apoptosis. Moreover, real-time PCR analysis showed that VCR-induced cytotoxicity was augmented by AAE through alteration of Bax, and Bcl-2 mRNA expression. Conclusion: Overall, owing to the nontoxic nature of AAE and its explicit role in enhancing VCR effectiveness, our study provided new insight into the development of a novel combinatorial approach in ALL using natural herbs. The practical implication of the research requires further investigation through clinical trials, opening avenues for forthcoming treatment improvements.

Proteasome Inhibition by Carfilzomib Induced Apotosis and Autophagy in a T-cell Acute Lymphoblastic Leukemia Cell Line.

T-cell acute lymphoblastic leukemia is an aggressive hematologic malignancy which is usually associated with unfavorable prognosis particularly in patients with refractory/relapsed disease. Therefore, development of novel therapeutic strategies is highly required for improving the outcome of these patients. Although there are several studies evaluating the efficacy of proteasome inhibitors on acute lymphoblastic leukemia of B-cell lineage, the data are still limited regarding T-cell acute lymphoblastic leukemia. Here, we tried to investigate the effects of the proteasome inhibition by carfilzomib on the induction of apoptosis and autophagy in Molt4 cells. The effect of carfilzomib in combination with dexamethasone in Molt4, as a glucocorticoid-resistant T-cell acute lymphoblastic leukemia cell line, was also assessed. Our data showed that carfilzomib can induce both apoptosis and autophagy in Molt4 cells. Furthermore, we found that carfilzomib is a potent inducer of reactive oxygen species production and also induces G2/M phase cell cycle arrest in Molt4 cells. Concomitant treatment with carfilzomib and dexamethasone demonstrated that carfilzomib can synergistically enhance the cytotoxic effect of dexamethasone on Molt4 cells. Furthermore, co-treatment of the cells with carfilzomib and dexamethasone increased the induction of autophagy as compared with each drug alone. In conclusion, our results are suggestive of the effectiveness of carfilzomib on Molt4 cells as a model of GC-resistant T-cell acute lymphoblastic leukemia.

The clinical significance of CDX2 in leukemia: A new perspective for leukemia research.

CDX2 gene encodes a transcription factor involved in primary embryogenesis and hematopoietic development; however, the expression of CDX2 in adults is restricted to intestine and is not observed in blood tissues. The ectopic expression of CDX2 has been frequently observed in acute myeloid and lymphoid leukemia which in most cases is concomitant with poor prognosis. Induction of CDX2 in mice leads to hematologic complications, showing the leukemogenic origin of this gene. CDX2 plays significant role in the most critical pathways as the regulator of important transcription factors targeting cell proliferation, multi-drug resistance and survival. On the whole, the results indicate that CDX2 has the potential to be suggested as the diagnostic marker in hematologic malignancies. This review discusses the role of aberrant expression of CDX2 in the prognosis and the response to treatment in patients with different leukemia in clinical reports in the recent decades. The improvement in this regard could be of high importance in diagnosis and treatment methods.

Centaurea albonitens extract enhances the therapeutic effects of Vincristine in leukemic cells by inducing apoptosis.

Drug-induced toxicities and dose-related side effects are the major challenges in the conventional cancer therapy by the chemo drugs. On the other hand, herbal derivatives have obtained a great research interest in the field of therapeutic applications because of their more favorable specifications including less toxicity, cost-effective and more physiologically compatible than the chemical drugs. For this purpose, we evaluated methanolic extract prepared from Centaurea albonitens Turrill alone and in combination with Vincristine (VCR) for its potential cytotoxic effects in NALM-6, REH, NB4 and KMM-1 cell lines by using the various approaches. Centaurea genus is one of the current medicinal plants, which has used in traditional medicine, However, there are rare studies to examine its anticancer properties against hematologic malignant cells. In this study, we demonstrated Centaurea albonitens extract (CAE) induces cytotoxicity through G0/G1 phase arrest followed by apoptosis in a dose- and time- dependent manner, although with varying efficiency. Interestingly, normal cells didn't exhibit significant cytotoxicity after CAE treatment. Moreover, we found that low dose of CAE enhances anti-cancer effects of VCR in pre-B ALL cell lines (NALM-6 and REH). Further investigations validated synergistic anticancer activities of VCR and CAE through inducing apoptosis without significant cell cycle arrest. Taken together, our results demonstrated for the first time that the methanolic extract of Centaurea albonitens can be considered as a potential anticancer agent and/or an enhancer of chemotherapeutic sensitivity of VCR.