Caspase Dependent and Independent Anti-hematological Malignancy Activity of AMHA1 Attenuated Newcastle Disease Virus.

Hematological malignancies remain one of the leading causes of death worldwide despite advances in cancer therapeutics. Newcastle disease virus (NDV) is a member of Paramyxoviridae that elicits considerable interest as an anticancer agent because it can replicate up to 10 000 times faster in human cancer cells than in most normal cancer cells. Several NDV strains reportedly induce the cytolysis of cancerous cell lines. The attenuated Iraqi strain (AMHA1) of NDV is a novel oncolytic agent with promising antitumor characteristics, including apoptosis induction. This study aimed to evaluate the ability of the AMHA1 NDV strain to induce apoptotic cell death in hematological tumors through caspase-dependent or independent apoptotic pathways. The cytolytic effects of AMHA1 NDV strains of different multiplicity of infection (MOIs) (20, 15,10, 5, 3, 1, 0.5, and 0.1 )and exposure for all hematological malignancy cell lines (human non-Hodgkin lymphoma SR and human multiple myeloma (COLO 677) and human monocytic leukemia THP1) have been determined through a microtetrazolium (MTT) assay. Propidium iodide and acridine orange (AO/PI) double staining were used to examine the ability of attenuated NDV strain to induce apoptosis in infected cells under a fluorescence microscope and to quantify the percentage of apoptosis induction. Quantitative immunocytochemistry assay was further used to study the caspase-dependent and independent protein expression levels in infected and control cells. Cells treated with NDV strains showed a higher cell-death percentage than untreated cells as quantified by the MTT assay. AO/PI results revealed that NDV exerted a powerful and significant effect on apoptosis induction (P<0.0001) in the human cancer cell lines tested in comparison with control cells. Immunocytochemistry in AMHA1 NDV- infected human hematological cell lines revealed a remarkable increase in the expression of caspase 8, 9 (dependent pathway), apoptosis-inducing factor, and endonuclease G (independent pathway) in comparison with untreated cells. This study demonstrated the role of the Iraqi NDV strain in inducing apoptosis through dependent and independent pathways in cancer cells and thus its high potential as an antitumor agent.

Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy.

Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou-Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies.

Antiglycation and antioxidant effect of carnosine against glucose degradation products in peritoneal mesothelial cells.

BACKGROUND/AIM: Toxicity with advanced glycation end products (AGEs) is a major problem in uremic patients. Treatment with peritoneal dialysis (PD) exacerbates AGE formation as a result of bioincompatibility of the conventional peritoneal dialysis fluid (PDF). The presence of glucose degradation products (GDPs) in PDF is the main cause of its bioincompatibility. Carnosine is an endogenous dipeptide with a powerful antiglycation/antioxidant activity. In an attempt to improve PDF biocompatibility, we evaluated the effect of carnosine in human peritoneal mesothelial cells (HPMC) incubated with PDF or GDPs in vitro. METHODS: HPMC were incubated for short or prolonged time with PDF in the presence or absence of carnosine. Similarly, HPMC were incubated in the same condition but with a combination of GDPs. Following the incubation, cells were tested for their viability, protein carbonyl content and reactive oxygen species (ROS) production. RESULTS: Results demonstrated a significant protective effect of carnosine to HPMC in both acute and chronic conditions with PDF or GDPs as judged by the enhancement of cell viability, preserved protein from modification and decreased ROS production. CONCLUSION: Carnosine enhanced HPMC viability against the toxic effect of GDPs probably through protection of cellular protein from modification and from ROS-mediated oxidative damage. The salutary effect of carnosine may render it a desirable candidate for improving PDF biocompatibility and reducing AGE complications in PD patients.