Describing a novel chemotherapeutic drug formulated by Diosmin for the treatment of acute lymphoblastic leukemia and diabetes mellitus

IntroductionDiosmin is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features. Acute leukemia is a common type of cancer that is caused in the blood.Material and methodsAlpha amylase activity was determined by a method adapted from the work of Taha et al.ResultsIn this study, we examined its effect on some important enzymes, the IC50 values were 196.07 for Aldose reductase, and 76.40 for alpha amylase. The molecular docking study was performed to assess the binding affinity and biological activities of diosmin in the presence of alpha amylase and aldose reductase. The results of the docking study indicated that diosmin has a remarkable binding affinity to these enzymes with a docking score of -9.768 and -140469 for alpha-amylase and aldose reductase, respectively. Therefore, this compound could be used as a potential inhibitor for these enzymes. In the cellular and molecular part of the recent study, the treated cells with Diosmin were assessed by MTT assay for 48h about the cytotoxicity and anti-human acute lymphoblastic leukemia properties on HL-60, Clone 15 HL-60, HL-60/MX1, and HL-60/MX2 cell lines. The IC50 of Diosmin were 466, 323, 502, and 537 µg/mL against HL-60, Clone 15 HL-60, HL-60/MX1, and HL-60/MX2 cell lines, respectively.ConclusionsThe viability of acute lymphoblastic leukemia cell lines reduced dose-dependently in the presence of Diosmin. It appears that the anti-human acute lymphoblastic leukemia effect of Diosmin is due to their antioxidant effects.

Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia

Leukemogenesis is characterized by chromosomal rearrangements with additional molecular disruptions, yet the cooperative mechanisms are still unclear. Using whole-exome sequencing of a pair of monozygotic twins discordant for childhood acute lymphoblastic leukemia (ALL) with ETV6-RUNX1 (E/R) gene fusion successively after birth, we identified the R209C mutation of G protein subunit alpha o1 (GNAO1) as a new ALL risk loci. Moreover, GNAO1 missense mutations are only recurrent in ALL patients and are associated with E/R fusion. Ectopic expression of the GNAO1 R209C mutant increased its GTPase activity and promoted cell proliferation and cell neoplastic transformation. Combined with the E/R fusion, the GNAO1 R209C mutant promoted leukemogenesis through activating PI3K/Akt/mTOR signaling. Reciprocally, activated mTORC1 phosphorylated p300 acetyltransferase, which acetylated E/R and thereby enhanced the E/R transcriptional activity of GNAO1 R209C. Thus, our study provides clinical evidence for the functional cooperation of GNAO1 mutants and E/R fusion, suggesting GNAO1 as a potential therapeutic target in human leukemia.

Induction of Cell Death in the Human Acute Lymphoblastic Leukemia Cell Line Reh by Infection with Rotavirus Isolate Wt1-5

Cancer is a major health problem that poses a great challenge to health care systems worldwide. Tools for cancer treatment have rapidly advanced in recent years, resulting in therapeutic strategies which are alternative and complementary to conventional treatment. To identify the cell surface receptors used by a tumor cell-adapted rotavirus and the cell death markers induced by its infection, we use Wt1-5, a rotavirus isolate recently adapted to tumor cells, to infect the human acute lymphoblastic leukemia cell line, Reh. The expression of cell surface receptors used by Wt1-5 was determined using flow cytometry and an antibody blocking assay to test for their implication in virus infection. Viral antigens and cell death markers induced by rotavirus infection were followed by flow cytometric analysis. The present study showed that rotavirus Wt1-5 was able to use cell surface proteins such as heat shock proteins (HSPs) 90, 70, 60 and 40, Hsc70, PDI and integrin β3. Rotavirus Wt1-5 induced cytotoxic effects including changes in cell membrane permeability, alteration of mitochondrial membrane potential, DNA fragmentation and activation of cell death signaling. Wt1-5 deserves to be further studied as a candidate oncolytic agent due to its ability to induce apoptosis in lymphoblastic leukemia-derived cells.

Evaluation of the combined effects of doxorubicin and bortezomib on the human acute lymphoblastic leukemia cell line

Increasing numbers of oncological patients and growing drug resistance ensure that new methods of cancer treatment are intensively sought. Combining drugs for a synergistic effect is one of several possible ways to mitigate this problem. This leads to reducing the effective drug dose and the occurrence of side effects. Doxorubicin (DOX) is an antineoplastic agent that has several mechanisms of action. DOX intercalates between base pairs of DNA helix, inhibits topoisomerase II and also forms reactive oxygen species. Bortezomib (BZT) is an antitumor agent belonging to the group of proteasome inhibitors. It has been observed that BZT triggers an oxidative stress response in vitro and in vivo. Accumulation of oxidatively damaged proteins and the simultaneously blocking of the proteasome can be very damaging to the tumour cell. For this reason, the aim of the study was to assess the potentially synergistic effect of DOX and BZT on human acute lymphoblastic leukemia (ALL). In the work, the cells were treated with both agents and their combinations and the effect was evaluated on the basis of morphological assessment, MTT assay and level of reduced glutathione measurement. The study has shown that on acute lymphoblastic leukemia cells, synergistic effects came about in the combination of 1nM BZT with a wide range of concentrations of DOX. Herein, the visible, coactive effect of DOX and BZT was observed on oxidative stress levels. This phenomenon can be essential in blunting the possibility of rapid manifestation of resistance seen in BZT monotherapy. In addition, the needed very low concentrations of DOX reduce the risk of therapy side effect.