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Anticancer Compound ABT-263 Accelerates Apoptosis in Virus-Infected Cells and Imbalances Cytokine Production and Lowers Survival Rates of Infected Mice

Laura Kakkola, Oxana V. Denisova, Janne Tynell, Johanna Viiliäinen, Tine Ysenbaert, Rita C. Matos, Ashwini Nagaraj, Tiina Öhman, Suvi Kuivanen, Henrik Paavilainen, L Feng, Bhagwan Yadav, Ilkka Julkunen, Olli Vapalahti, Veijo Hukkanen, Veijo Hukkanen, Jakob Stenman, Tero Aittokallio, Emmy W. Verschuren, Päivi Ojala, Tuula Nyman, Xavier Saelens, K. Dzeyk, Denis Kainov, Anticancer Compound ABT-263 Accelerates Apoptosis in Virus-Infected Cells and Imbalances Cytokine Production and Lowers Survival Rates of Infected Mice. Cell Death and Disease 4, 1–13, 2013.

http://dx.doi.org/10.1038/cddis.2013.267

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.

BibTeX entry:

@ARTICLE{jKaDeTyViYsMaNaOKuPaFeYaJuVaHuVeStAiVeOjNySaDzKa13,
  title = {Anticancer Compound ABT-263 Accelerates Apoptosis in Virus-Infected Cells and Imbalances Cytokine Production and Lowers Survival Rates of Infected Mice},
  author = {Kakkola, Laura and Denisova, Oxana V. and Tynell, Janne and Viiliäinen, Johanna and Ysenbaert, Tine and Matos, Rita C. and Nagaraj, Ashwini and Öhman, Tiina and Kuivanen, Suvi and Paavilainen, Henrik and Feng, L and Yadav, Bhagwan and Julkunen, Ilkka and Vapalahti, Olli and Hukkanen, Veijo and Veijo Hukkanen and Stenman, Jakob and Aittokallio, Tero and Verschuren, Emmy W. and Ojala, Päivi and Nyman, Tuula and Saelens, Xavier and Dzeyk, K. and Kainov, Denis},
  journal = {Cell Death and Disease},
  volume = {4},
  pages = {1–13},
  year = {2013},
  keywords = {innate immunity; apoptosis; Bcl-xL; infection; cytokines; virus},
  ISSN = {2041-4889},
}

Belongs to TUCS Research Unit(s): Biomathematics Research Unit (BIOMATH)

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