The pharmacological NFkappaB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activation.
A growing body of evidence suggests the inhibition of NFkappaB as a strategy to induce cell death in tumor cells. In this work, we evaluated the effects of the pharmacological NFkappaB inhibitors BAY117082 and MG132 on leukemia cells apoptosis. BAY117082 and MG132 presented potent apoptotic effects compared to inhibitors of MAPKs, EGFR, PI3K/Akt, PKC and PKA signaling pathways. Non-tumor peripheral blood cells were insensitive to BAY117082 and MG132 apoptotic effects. BAY117082 and MG132-induced apoptosis was dependent on their ability to increase ROS as a prelude to mitochondria membrane potential (MMP) depolarization, permeability transition pore opening and cytochrome c release. Antioxidants blocked MG132 and BAY117082 effects on ROS, MMP and cell death. Although apoptotic markers as phosphatidylserine externalization, chromatin condensation and sub-G1 were detected in BAY117082-treated cells, caspases activation did not occur and apoptosis was insensitive to caspase inhibitors, suggesting a caspase-independent mechanism. In contrast, MG132 induced classical apoptosis through ROS-mitochondria and subsequent caspase-9/caspase-3 activation. At sub-apoptotic concentrations, BAY117082 and MG132 arrested cells in G2/M phase of the cell cycle and blocked doxorubicin-induced NFkappaB, which sensitized doxorubicin-resistant cells. Data suggest that the NFkappaB inhibitors MG132 and BAY117082 are potential anti-leukemia agents.
Zanotto-Filho
Alfeu
A
Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, UFRGS, Rio Grande do Sul, Brazil. ohalceu@yahoo.com.br
Delgado-Cañedo
Andrés
A
Schröder
Rafael
R
Becker
Matheus
M
Klamt
Fábio
F
Moreira
José Cláudio Fonseca
JC
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D007976:Leupeptins / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology*; D013997:Time Factors; D020298:U937 Cells
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D007976:Leupeptins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016328:NF-kappa B; D009570:Nitriles; D017382:Reactive Oxygen Species; D013450:Sulfones; D004317:Doxorubicin; D045304:Cytochromes c; D020169:Caspases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde