Two COX-2 inhibitors induce apoptosis in human erythroleukemia K562cells by modulating NF-κB and FHC pathways

Abstract

BackgroundLeukemia is distinguished by abnormal proliferation of leukocytes. Although there has been some progress in developing novel cancer therapies, no significant improvement was observed in the overall survival rate over the last decade. Selective cyclooxygenase-2 (COX-2) inhibitors are known to inhibit tumor growth by exerting antimetastatic and antiangiogenic effects through inhibition of COX –dependent and independent pathways. The ability of two new triaryl-oxadiazole derivatives, compounds A (3-(4-chlorophenyl) -5-(4-flurophenyl)-4-Phenyl-4,5-dihydro-1,2,4-oxadiazole) and B (3,5-bis(4-chlorophenyl)-4-Phenyl-4,5-dihydro-1,2,4-oxadiazole), to induce apoptosis in human erythroleukemia K562 cells was evaluated and the upstream mechanism was investigated.MethodsK562 cells were treated with compounds A and B at their IC50 concentrations and analyzed by DAPI staining and Annexin-V-FLUOS labelling solution. Nuclear factor kappa-B (NF-κB) activation was evaluated by TransAM kit. Cyclooxygenase-2 (COX-2), Caspase-3, Bax, Bcl-2, ferritin heavy chain (FHC), extra cellular signal-regulated kinase (ERK), p-ERK and early growth response protein-1 (Egr1) levels were determined using Western blotting, while c-Myc mRNA level was investigated by RT-PCR.ResultsChanges in nuclear morphology and the increased annexin-V/PI staining revealed the apoptotic cell death in compounds A- and B-treated K562 cells. A significant reduction in NF-κB activity as well as FHC and p-ERK levels were detected in these cells. No change was observed in the levels of Bax, Bcl-2, Caspase-3, COX-2, c-Myc and Egr1, following treatment with the two compounds. Collectively, compounds A and B potentiate apoptosis as shown by DAPI staining, flowcytometry, FHC and p-ERK downregulation and NF-κB inactivation.ConclusionTwo compounds induce apoptosis in a COX-2-independent manner which also appears to be independent from mitochondria, caspase and c-Myc/Egr1 pathways.

Prostate-Specific Membrane Antigen-Targeted Site-Directed Antibody-Conjugated Apoferritin Nanovehicle Favorably Influences In Vivo Side Effects of Doxorubicin

“…The ideal nanocarrier needs to not only be non-toxic but also biocompatible and biodegradable 7 . These properties are important for both the subjects involved in the treatment and the general public since the nanoparticles are often excreted into waste water and can pose a threat to the environment 8 . Many different materials have been studied for the preparation of drug nanocarriers, both organic and inorganic 9 .…”

“…Inorganic exogenous materials are usually not biodegradable and can be accumulated in an organism following repeated administration or prematurely captured in organs of the reticuloendothelial system 10 . They can also cause inflammatory response or neurotoxic reactions 8 . Organic exogenous particles also have some drawbacks.…”

Gender differences in substance use patterns and disorders among an Iranian patient sample receiving methadone maintenance treatment

“…However, the main focus has been placed upon the treatment of opioid dependence in Iran, and there exist around 5,000 Outpatient Buprenorphine or MMT clinics, that put a population of about 500,000people under treatment ( 4 , 5 ). On the other hand, substance use and dependence are also increasing among women and, accordingly, specific clinics are being established in Iran for the treatment of opioid use among women ( 6 ). Normally, the number of women referring to MMT clinics is on the rise while women constitute about 10% of the patients referring to the MMT clinics now ( 7 ).…”

Multi-criteria decision analysis for health technology assessment: addressing methodological challenges to improve the state of the art

“…Evaluated health interventions included public health programmes [91], primary care programmes [92, 93], community care programmes [94], screening strategies [95], mental health services [96], smoking cessation interventions [97] and types of medical care to be covered [98, 99]. One study evaluated both pharmaceuticals and surgical technologies for priority setting purposes [100].…”