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.
Highlights
Leukemia is distinguished by abnormal proliferation of leukocytes
We have recently reported that two compounds with triaryl-oxadiazole structures known as compounds A (3- (4-chlorophenyl) -5-(4-flurophenyl)-4-Phenyl-4,5dihydro-1,2,4-oxadiazole) and B (3,5-bis(4- chlorophenyl)-4-Phenyl-4,5-dihydro-1,2,4-oxadiazole) (Fig. 1) show significant biological features such as antiproliferative activity with considerable IC50 values (21.66 and 22.23 μM) in human erythroleukemia (K562) cell line after a 24 h treatment [11]
Apoptosis induction in K562 cells following compounds A and B treatments In order to examine whether compounds A and B exhibit cytotoxicity in K562 cells through apoptosis, DAPI staining analysis was undertaken in order to observe morphological changes in K562 cells following treatment with compounds A(21.66 μM) and B(22.23 μM) for 8 and 16 h (Fig. 2)
Summary
Leukemia is distinguished by abnormal proliferation of leukocytes. 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-4,5dihydro-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. Celecoxib represents a 1, 2-di-aryl heterocyclic structure and used as an ideal lead compound for developing novel derivatives with potent apoptosis-inducing activity [9, 10]. We have recently reported that two compounds with triaryl-oxadiazole structures known as compounds A (3- (4-chlorophenyl) -5-(4-flurophenyl)-4-Phenyl-4,5dihydro-1,2,4-oxadiazole) and B (3,5-bis(4- chlorophenyl)-4-Phenyl-4,5-dihydro-1,2,4-oxadiazole) (Fig. 1) show significant biological features such as antiproliferative activity with considerable IC50 values (21.66 and 22.23 μM) in human erythroleukemia (K562) cell line after a 24 h treatment [11]. We examined the mechanism leading to apoptosis during treatment of K562 cell line with the two new celecoxib derivatives, compounds A and B
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