Inhibition of I?B? phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells.

ABSTRACT: Adult T cell leukemia/lymphoma (ATL) can be susceptible, at least transiently, to treatments with azidothymidine (AZT) plus IFN? and/or arsenic trioxide. However, the real role of AZT in this effect is still unclear. In fact, while reverse transcriptase (RT) inhibition could explain reduction of clonal expansion and of renewal of HTLV-1 infected cells during ATL progression, this effect alone seems insufficient to justify the evident and prompt decrease of the pro-viral load in treated patients. We have previously demonstrated that AZT is endowed with an intrinsic pro-apoptotic potential towards both peripheral blood mononuclear cells from healthy donors or some tumor cell lines, but this cytotoxic potential cannot be fully achieved unless I?B? phosphorylation is inhibited. Since the constitutive activation of NF-kappa B (NF-?B) appears a common biological basis of HTLV-1-infected cells, a pharmacological inhibition of I?B? phosphorylation seems a potential strategy for treating and preventing HTLV-1 related pathologies. In this study, we have demonstrated that a combination treatment with the I?B? phosphorylation inhibitor Bay 11-7085 and AZT induced increased levels of regulated cell death (RCD) by apoptosis compared to the single treatments in HTLV-1 infected cells of different origin. Importantly, levels of RCD were considerably higher in infected cells in comparison with the uninfected ones. Inhibition of NF-?B activation following the combined treatment was confirmed by analysis of both gel-shift and functional activity of the NF-?B complex proteins, p65/p52. Moreover, a transcriptional analysis revealed that the addition of Bay 11-7085 to AZT treatment in HTLV-1-infected cells modified their transcriptional profile, by inducing the upregulation of some pro-apoptotic genes together with the downregulation of some anti-apoptotic genes. Our data suggest that addition of adequate concentrations of I?B? phosphorylation inhibitor to therapeutic regimens including AZT could be a promising strategy in ATL.

SUBMITTER: Matteucci C 

PROVIDER: S-EPMC7028944 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature