1. Department of Pediatrics, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
2. Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
3. Departments of Genetics, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, 1700 Tulane Ave., New Orleans, LA 70112, USA
4. Departments of Pathology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, 1700 Tulane Ave., New Orleans, LA 70112, USA
Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human malignancies, particularly Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation while still lacking of effective therapeutic options. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic HGF/c-MET pathway in KSHV-related lymphoma cells. One of RR inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) effectively induced apoptosis of KSHV+ lymphomas and suppressed tumor progression in vivo. In the current study, we found that 3-AP treatment selectively inhibited the proliferation of KSHV-infected endothelial cells, the major cellular components of KS, through inducing DNA damage, reducing the levels of intracellular iron and reactive oxygen species (ROS) and increasing viral lytic gene expression. By using a KS-like nude mouse model, we found that 3-AP treatment significantly suppressed KSHV induced tumorigenesis in vivo. Taken together, our data demonstrate targeting RR by 3-AP may represent a promising strategy for improving the treatment of KS in future.
Keywords: KSHV, Kaposi's Sarcoma, Ribonucleotide reductase, 3-AP