Cellular growth inhibition by FK778 is linked to G1 arrest or S phase accumulation, dependent on the functional status of the retinoblastoma protein

Abstract

Abstract.The malononitrilamide FK778 is a novel immunosuppressive agent with antiproliferative activities. To gain insight into the molecular mechanism of FK778-mediated growth inhibition, we analyzed cells which differ in their p53 status and functionality of retinoblastoma protein (pRb). FK778 acted as a broad inhibitor of cell proliferation independent of the p53 or pRb status. However, the mechanism of FK778-mediated growth inhibition differed, leading either to cell cycle arrest in G1, or cell accumulation in S phase. This differential response was linked to the phosphorylation status of pRb. In addition, since FK778 was reported to exhibit antiviral activities, we analyzed the effect of FK778 on the growth stimulatory human papillomavirus (HPV)-16 and -18 E7 genes. Although growth of HPV-positive cells was strongly inhibited by FK778, we did not observe significant effects on viral E7 expression, indicating that the antiproliferative effect is not linked to an antiviral activity of FK778.

A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage

“…With regards to its effects on p53, leflunomide, although itself inactive as a DHODH inhibitor, was shown to elevate p53 protein levels in HeLa cells, a cell line where p53 is modulated by viral oncoproteins rather than mdm2 28 . In a previous study, a very high concentration (100 μM) of a teriflunomide analog was shown to accumulate p53 in non-infected cells 29 . Here we demonstrate that DHODH inhibitors such as members of the HZ series and brequinar activate a p53-dependent reporter in cells, and do so at low concentrations.…”

Effect of maintenance immunosuppressive drugs on virus pathobiology: evidence and potential mechanisms

“…Table shows the number of articles recovered from the PubMed database search on the antiviral properties of immunosuppressants, whereas Table illustrates the level and nature of evidence supporting the antiviral properties of each agent against different viruses. Because of space constraints, details of the effects of maintenance immunosuppressants on viruses with fewer than 50 publications (alpha‐herpesviruses, HHV6, 7, and 8, HBV, HPV, and parvovirus) can be found in Table .…”