Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Repurposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FLUAV), niclosamide against HSV-2, brequinar against human immunodeficiency virus 1 (HIV-1), and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vitro and in vivo tests.

Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development.

We demonstrated recently that different viruses and transfected viral RNA or plasmid DNA killed human non-malignant cells sensitized with Bcl-xL-specific inhibitor A-1155463. Here, we show that DNA-damaging agent 4-nitroquinoline-1-oxide (4NQO) killed human non-malignant as well as malignant cells and the small roundworm C. elegans when combined with A-1155463, but not with Bcl-2-or Mcl-1-specific agents. The synergistic effect of 4NQO-A-1155463 combination was p53 dependent and was associated with the release of Bad and Bax from Bcl-xL, indicating that Bcl-xL linked DNA damage response pathways, p53 signalling and apoptosis. Other anticancer drugs (i.e. amsacrine, SN38, cisplatin, mitoxantrone, dactinomycin. dinaciclib, UCN-01, bortezomib, and S63845), as well as birth-control drug 17α-ethynylestradiol, immunosuppressant cyclosporin, antiviral agent brincidofovir, DNA binding probes MB2Py(Ac), DB2Py(4) and DBPy(5) and UV radiation also killed A-1155463-sensitized non-malignant cells. Thus, we established a method to identify physical, chemical and biological factors, which trigger Bcl-xL-mediated apoptosis. The method could be used in the development of novel anticancer therapies based on systemic Bcl-xL-specific inhibitor and local radiation, oncolytic virus infection or chemotherapy.

Viruses are the major causes of acute and chronic infectious diseases in the world. According to the World Health Organization, there is an urgent need for better control of viral diseases. Re-purposing existing antiviral agents from one viral disease to another could play a pivotal role in this process. Here we identified novel activities of obatoclax and emetine against herpes simplex virus type 2 (HSV-2), human immunodeficiency virus 1 (HIV-1), echovirus 1 (EV1), human metapneumovirus (HMPV) and Rift Valley fever virus (RVFV) in cell cultures. Moreover, we demonstrated novel activities of emetine against influenza A virus (FluAV), niclosamide against HSV-2, brequinar against HIV-1, and homoharringtonine against EV1. Our findings may expand the spectrum of indications of these safe-in-man agents and reinforce the arsenal of available antiviral therapeutics pending the results of further in vivo tests.