Combined Inhibition of Bcl2 and Bcr-Abl1 Exercises Anti-Leukemia Activity but Does Not Eradicate the Primitive Leukemic Cells

Background: The management of Philadelphia Chromosome-positive (Ph+) hematological malignancies is strictly correlated to the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, these drugs do not induce leukemic stem cells death and their persistence may generate a disease relapse. Published reports indicated that Venetoclax, a selective BCL2 inhibitor, could be effective in Ph+ diseases, as BCL2 anti-apoptotic activity is modulated by BCR-ABL1 kinase. We, therefore, investigated if BCL2 inhibition, alone or combined with Nilotinib, a BCR-ABL1 inhibitor, affects the primitive and committed Ph+ cells survival. Methods: We used Ph+ cells isolated from leukemic patients at diagnosis. To estimate the therapeutic efficacy of BCL2 and BCR-ABL1 inhibition we employed long-term culture, proliferation and apoptosis assay. Immunoblot was used to evaluate the ability of treatment to interfere with the down-stream targets of BCR-ABL1. Results: Blocking BCL2, we observed reduced proliferation and clonogenic potential of CML CD34-positive cells and this cytotoxicity was improved by combination with BCR-ABL1 inhibitor. However, BCL2 inhibition, alone or in combination regiment with BCR-ABL1 inhibitor, did not reduce the self-renewal of primitive leukemic cells, while strongly induced cell death on primary Ph+ Acute Lymphoblastic Leukemia (ALL). Conclusion: Our results suggest that primitive CML leukemic cells are not dependent on BCL2 for their persistence and support that committed CML and Ph + ALL cells are dependent by BCL2 and BCR-ABL1 cooperation for their survival. The antileukemic activity of BCL2 and BCR-ABL1 dual targeting may be a useful therapeutic strategy for Ph+ ALL patients.

Genetic Relationship of Transcriptional Factor Genes in the Regulation of Cells Death in Arabidopsis: A Review

The leaf yellowing is the first visible sign of senescence, which starts at the margins of the leaf and progresses to the blade. Although, transcriptional factor family genes generally encode meticulous regulators which perform a range of functions in turns regulating the physiological and developmental mechanism of plant stature. However, the genetic relationship of TFs genes in regulating the cell death of Arabidopsis is well not understood to date. TFs family in a plant regulates various developmental and stress responses in underline pathways. In our review we observed the genetic relationship of TFs genes in regulations of cell death in Arabidopsis. Given that, programmed cell death (PCD) being an active process that includes the expression of hundreds of genes. It is speculated that many TFs are involved in the core elements of the regulatory network. There are only a few factors that are being demonstrated in involving the regulation of cell death, by evaluating the leaf senescence appearances of knocking of mutants and by identifying downstream target genes. In this review, we have focused on the manifold roles of TFs during genetic relationships and the regulation of cell death in Arabidopsis. We also deliberated how the transcription factors family gene regulates the cells’ death by different hormonal stress, environmental strain and their role in retrograde signaling. For deep understanding of regulatory molecular mechanisms of cell death in the plant, future research may be hypothesized to collect appropriate evidence and a detailed study may be implemented on the upstream pathway with a specific targeted gene that recognizes the stress signals involved in cell death in plants. Also, crosstalk between mitochondria and chloroplast is mainly being focused to better understand the regulations of cell death in plants. Present review concludes that regulating the cell death of Arabidopsis is very important for meeting future global food needs, crop yields. Overexpression of ERF transcription factors genes relating cell death of Arabidopsis confers broad-spectrum resistance to pathogens and other abiotic stresses and can also make transgenic plants resistant to drought, salinity and freezing.

STING-mediated Syk Signaling Attenuates Tumorigenesis of Colitis‑associated Colorectal Cancer Through Enhancing Intestinal Epithelium Pyroptosis

Background Stimulator of interferon genes (STING) has essential functions in the immune responses and can induce cancer cell apoptosis. However, it is not completely clear how STING plays a role in colitis-associated colorectal cancer (CAC) and whether it can trigger pyroptosis during the tumorigenesis of CAC. Methods To investigate the role of STING-modulated pyroptosis in the development of CAC, STING knockout and Wild type mice were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to establish a murine CAC model. STING pharmacological agonist was used to further study the functions of STING signaling in the tumorigenesis. Moreover, STING endogenous ligand was employed to verify the effects of STING in human colon cancer cells. Results STING deficiency mice were more susceptible to CAC by reducing pyroptosis of tumor cells, whereas overactivation of STING with the agonist suppressed tumorigenesis of CAC. STING also managed CAC development by modulating tumor cells proliferation, adhesion, and invasion, as well as inflammatory response. The ex vivo studies indicated that STING could induce pyroptosis via spleen tyrosine kinase (Syk), and Syk knockdown weakened such pyroptotic tumor cells death. In addition, the visible physical interaction between STING and Syk was observed in colorectal tumor samples of CAC patients. Conclusions STING-mediated Syk signaling may regulate the tumorigenesis of CAC by modulating pyroptosis of tumor cells, and modulation of STING/Syk serves as a novel therapeutic strategy for CAC therapy.

Newly-found functions of metformin for the prevention and treatment of age-related macular degeneration

Metformin (MET), a first-line oral agent used to treat diabetes, exerts its function mainly by activating adenosine monophosphate-activated protein. The accumulation of oxidized phospholipids in the outer layer of the retina plays a key role in retinal pigment epithelium (RPE) cells death and the formation of choroidal neovascularization (CNV), which mean the development of age-related macular degeneration (AMD). Recent studies have shown that MET can regulate lipid metabolism, inhibit inflammation, and prohibit retinal cell death and CNV formation due to various pathological factors. Here, newly discovered functions of MET that may be used for the prevention and treatment of AMD were reviewed.

New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na2[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5’-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5’-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells’ death by apoptosis and necrosis.

The “ARTS” of Cell Death in Service of Life: How Do We Force Cancer Cells to Commit Suicide?

Every cell in our body contains a “self-destruction” program. This cell death is a critical process allowing replacement of damaged cells with healthy ones to prevent wide range of diseases. When the cell’s death mechanism gets “stuck” and is not activated, cancer can result. In healthy cells there is a balanced system of proteins, some of which activate the normal death mechanism, and some of which inhibit this process. This is like the system of gas and brakes in a car. Researchers have found that cancer cells lack a protein, called ARTS, which is crucial for activating the cells’ death mechanism. The lack of ARTS causes cancer cells to escape death and become “immortal.” Small ARTS-like molecules have been discovered that can penetrate cancerous cells and reactivate the cell death program, effectively making the cancer cells “commit suicide.” We envision that these ARTS-like molecules will provide novel therapy for cancer.