Therapeutic approaches for relapsed/refractory adult acute lymphoblastic leukemia (ALL), a review on monoclonal antibodies and targeted therapies.

Acute lymphoblastic leukemia (ALL) is the malignant transformation of lymphoid progenitors that affects both children and adults. Although the outcome of pediatric patients has been improved dramatically, there are still many challenges in the treatment of adults. Patients with primary resistant or relapsed disease have the worst outcome and despite the administration of intensified multi-agents chemotherapies, the outcome of this group remains very poor. Accordingly, the development of novel therapeutic options is considered necessary. Having a comprehensive insight into the pathophysiology of ALL and aberrant signaling pathways is crucial for introducing effective targeted therapies. Combination therapies with new drugs and innovative targeted therapies with the aim of affecting the main aberrant signaling pathways in the disease are considered as new approaches. Here we tried to have a comprehensive review on the potential molecular targets in the treatment of refractory/relapsed ALL and the current therapeutic agents.

Britannin a Sesquiterpene Lactone from Inula aucheriana Exerted an Anti-leukemic Effect in Acute Lymphoblastic Leukemia (ALL) Cells and Enhanced the Sensitivity of the Cells to Vincristine.

Since chemotherapy drugs have dose-related side effects, there is still a need for finding new agents with suitable cytotoxic effects without any harmful effects. For this purpose, we evaluated the cytotoxic effects of Britannin that is a Sesquiterpene Lactone compound Inula aucheriana, alone or in combination with Vincristine (VCR), on Acute Lymphoblastic Leukemia (ALL)-derived MOLT-4 cells. In this study, we found that Britannin decreased the viability of MOLT-4 cells with the IC50 Values of 2 µM, but had no cytotoxic effects on normal cells or Peripheral Blood Mononuclear Cells (PBMCs). Our results also showed that Britannin decreased the proliferation of MOLT-4 cells by preventing the transition of the cells from the S phase of the cell cycle through the up-regulation of p21 and p27. Moreover, this agent induced ROS-mediated apoptosis by altering the expression of Bax, Bim, Caspase3, Bcl2, and XIAP. Britannin also produced a synergistic effect with Vincristine in MOLT-4 cells. Taken together, the results of this study showed for the first time that Britannin, as a natural Sesquiterpene Lactone, has cytotoxic effects that could be considered as an anti-leukemic agent in the treatment of ALL. However, there is still a demand for further studies that examine the efficacy and the safety of this purified compound.

Britannin, a sesquiterpene lactone induces ROS-dependent apoptosis in NALM-6, REH, and JURKAT cell lines and produces a synergistic effect with vincristine.

BACKGROUND: Britannin, a Sesquiterpene Lactone isolated from Inula aucheriana, has recently gained attraction in the therapeutic fields due to its anti-tumor properties. This study was designed to evaluate the effect of this agent on Acute Lymphoblastic Leukemia (ALL) cell lines, either as a monotherapy or in combination with Vincristine (VCR). METHODS AND RESULTS: To determine the anti-leukemic effects of Britannin on ALL-derived cell lines and suggest a mechanism of action for the agent, we used MTT assay, Annexin-V/PI staining, ROS assay, and real-time PCR analysis. Moreover, by using a combination index (CI), we evaluated the synergistic effect of Britannin on Vincristine. We found that unlike normal Peripheral Blood Mononuclear Cells (PBMCs) and L929 cells, Britannin reduced the viability of NALM-6, REH, and JURKAT cells. Among tested cells, NALM-6 cells had the highest sensitivity to Britannin, and this agent was able to induce p21/p27-mediated G1 cell cycle arrest and Reactive Oxygen Specious (ROS)-mediated apoptotic cell death in this cell line. When NALM-6 cells were treated with Nacetyl-L-Cysteine (NAC), a scavenger of ROS, Britannin could induce neither apoptosis nor reduce the survival of the cells suggesting that the cytotoxic effect of Britannin is induced through ROS-dependent manner. Moreover, we found that a low dose of Britannin enhanced the effect of Vincristine in NALM-6 cells by inducing apoptotic cell death via altering the expression of apoptotic-related genes. CONCLUSIONS: Overall, our results proposed a mechanism for the cytotoxic effect of Britannin, either as a single agent or in combination with Vincristine, in NALM-6 cells.

Assessment the knowledge of blood transfusion in Iranian nurses of Tehran's hospitals.

OBJECTIVE: To investigate the knowledge of nurses about pre and post blood transfusion processes. BACKGROUND: To ensure a safe blood transfusion, apart from the role of blood banking to perform safe donation, attention must be paid to equally important but rather neglected factors including nursing practice and knowledge of blood transfusion. METHOD AND MATERIALS: Data was collected using a valid blood transfusion questionnaire consisting of 43 questions. We analysed data using SPSS 22. Percentages and analytical statistics such as Mann-Whitney, Kruskal-Wallis were used to report the results. The significant level of p-value was assumed to be <0.05. RESULTS: In this study, 325 nurses participated and their knowledge scores ranged from 24% to 85% (mean 56.16, standard deviation: 5.92) and the majority of nurses lacked knowledge in pre-transfusion activities. The analysis also revealed there was a significant correlation between the knowledge score and academic degree. Out of all nurses, 48% (N = 156) declared that they need further training in haemovigilance. As the minimum and maximum scored questions, it was revealed that only 39 nurses (12%) have enough knowledge to act properly in case of ambiguous orders; on the other hand, 94% (N = 304) have sufficient knowledge of the agents administered with transfusion. A large proportion of the involved nurses are unaware of the risk of improper identification. CONCLUSION: All the efforts taken to prepare a safe and matched blood unit would be futile by inattentive administration of blood. That is why mandatory ongoing blood transfusion training for nurses is required urgently.

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.

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.