title: Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected mice.
abstract: ABT-263 and its structural analogues ABT-199 and ABT-737 inhibit B-cell lymphoma 2 (Bcl-2), BCL2L1 long isoform (Bcl-xL) and BCL2L2 (Bcl-w) proteins and promote cancer cell death. Here, we show that at non-cytotoxic concentrations, these small molecules accelerate the deaths of non-cancerous cells infected with influenza A virus (IAV) or other viruses. In particular, we demonstrate that ABT-263 altered Bcl-xL interactions with Bcl-2 antagonist of cell death (Bad), Bcl-2-associated X protein (Bax), uveal autoantigen with coiled-coil domains and ankyrin repeats protein (UACA). ABT-263 thereby activated the caspase-9-mediated mitochondria-initiated apoptosis pathway, which, together with the IAV-initiated caspase-8-mediated apoptosis pathway, triggered the deaths of IAV-infected cells. Our results also indicate that Bcl-xL, Bcl-2 and Bcl-w interact with pattern recognition receptors (PRRs) that sense virus constituents to regulate cellular apoptosis. Importantly, premature killing of IAV-infected cells by ABT-263 attenuated the production of key pro-inflammatory and antiviral cytokines. The imbalance in cytokine production was also observed in ABT-263-treated IAV-infected mice, which resulted in an inability of the immune system to clear the virus and eventually lowered the survival rates of infected animals. Thus, the results suggest that the chemical inhibition of Bcl-xL, Bcl-2 and Bcl-w could potentially be hazardous for cancer patients with viral infections.
authors.affiliation: The Institute for Molecular Medicine Finland, FIMM, Helsinki 00290, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Kakkola
authors.forename: O V
authors.initials: OV
authors.lastname: Denisova
authors.forename: J
authors.initials: J
authors.lastname: Tynell
authors.forename: J
authors.initials: J
authors.lastname: Viiliäinen
authors.forename: T
authors.initials: T
authors.lastname: Ysenbaert
authors.forename: R C
authors.initials: RC
authors.lastname: Matos
authors.forename: A
authors.initials: A
authors.lastname: Nagaraj
authors.forename: T
authors.initials: T
authors.lastname: Ohman
authors.forename: S
authors.initials: S
authors.lastname: Kuivanen
authors.forename: H
authors.initials: H
authors.lastname: Paavilainen
authors.forename: L
authors.initials: L
authors.lastname: Feng
authors.forename: B
authors.initials: B
authors.lastname: Yadav
authors.forename: I
authors.initials: I
authors.lastname: Julkunen
authors.forename: O
authors.initials: O
authors.lastname: Vapalahti
authors.forename: V
authors.initials: V
authors.lastname: Hukkanen
authors.forename: J
authors.initials: J
authors.lastname: Stenman
authors.forename: T
authors.initials: T
authors.lastname: Aittokallio
authors.forename: E W
authors.initials: EW
authors.lastname: Verschuren
authors.forename: P M
authors.initials: PM
authors.lastname: Ojala
authors.forename: T
authors.initials: T
authors.lastname: Nyman
authors.forename: X
authors.initials: X
authors.lastname: Saelens
authors.forename: K
authors.initials: K
authors.lastname: Dzeyk
authors.forename: D E
authors.initials: DE
authors.lastname: Kainov
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D009980:Influenza A virus / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D016207:Cytokines; D013449:Sulfonamides; C528561:navitoclax