The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication

Abstract

Human cytomegalovirus (HCMV) is a major pathogen in immunocompromised individuals. Here, non-toxic concentrations of the anti-cancer kinase inhibitor sorafenib were shown to inhibit replication of different HCMV strains (including a ganciclovir-resistant strain) in different cell types. In contrast to established anti-HCMV drugs, sorafenib inhibited HCMV major immediate early promoter activity and HCMV immediate early antigen (IEA) expression. Sorafenib is known to inhibit Raf. Comparison of sorafenib with the MEK inhibitor U0126 suggested that sorafenib inhibits HCMV IEA expression through inhibition of Raf but independently of signaling through the Raf downstream kinase MEK 1/2. In concordance, siRNA-mediated depletion of Raf but not of MEK-reduced IEA expression. In conclusion, sorafenib diminished HCMV replication in clinically relevant concentrations and inhibited HCMV IEA expression, a pathophysiologically relevant event that is not affected by established anti-HCMV drugs. Moreover, we demonstrated for the first time that Raf activation is involved in HCMV IEA expression.

Human Cytomegalovirus IE1 Protein Disrupts Interleukin-6 Signaling by Sequestering STAT3 in the Nucleus

“…As a result, STAT3 inhibitors are being developed and are currently entering clinical trials as anticancer agents (71). Several FDA-approved compounds have been shown to inhibit STAT3 activity, such as Celebrex and Sorafenib (72)(73)(74), which also inhibit HCMV replication in vitro (75,76). Overall, our studies indicate that HCMV manipulates STAT3 to promote an environment that supports efficient viral DNA replication, and the findings implicate STAT3 as a possible target for anti-HCMV antiviral research.…”

Cytomegalovirus-specific cytokine-induced killer cells: concurrent targeting of leukemia and cytomegalovirus

“…All cell lines were cultured according to the manufacturer's instructions. Human foreskin fibroblasts were infected with a clinical isolate of human CMV (Strain Hi91) [26] at a multiplicity of infection of 2 at 37 C for 48 h. Subsequently, the input virus was removed and the fibroblasts were maintained in culture medium for the cytotoxic assay.…”

The role of Raf-1 kinase in diabetic retinopathy

“…Sorafenib (BAY 43 --9006), a Raf kinase/VEGF-R2 inhibitor has already been approved for treatment of renal cancer and is being tested for breast cancer [61]. It also inhibits the proliferation in tumor cell lines, and diminishes the replication of human cytomegalovirus, a major pathogen in immunocompromised individuals [62]. In addition, Sorafenib has recently entered Phase III clinical testing with promising signs of anti-cancer efficacy, and a very tolerable safety profile.…”