Our data reveal the novel (-)-Calyculin A biological activity observation that proteasome inhibition administered in combination with RA induces apoptosis in stem-cell like cells of neuroblastoma cell lines. The combined effects of RA/MG132 were more potent at reducing the stem-like cell population than either compound alone and moreover, impaired their capacity to form neurospheres. Therefore, we predict that this combined treatment might also have a positive impact in vivo in animal models. In human acute myeloid leukemia cells, bortezomib also sensitizes to RA-induced differentiation. However, our results also show increased apoptosis, suggesting that the molecular targets between these two diseases might be different, such as the activation of the JNK pathway, or on whether bortezomib is given after or concomitantly with RA. Since cancer stem cells are frequently resistant to conventional GNF-6231 therapy and are responsible for relapse, our results suggest that dual therapy might be beneficial for improving the outcome of patients with high-risk neuroblastoma. RA is the current standard treatment in the control of minimal residual disease in high-risk neuroblastoma patients and Bortezomib is already approved by EMA/FDA. Development of therapies for pediatric cancers is complicated by the rarity of these diseases with respect to the total population and the fact that only a limited number of drugs can be tested. Hence, drug combination therapies, particularly with drugs that are already approved, may play a key role in future neuroblastoma treatment strategies. Members of the Flavivirus genus, such as Dengue virus, Yellow Fever virus, West Nile virus, Tick-borne encephalitis virus, and Japanese encephalitis virus are ss-RNA arthropod-borne viruses that can cause serious human disease, including meningitis, myelitis, encephalitis, and hemorrhagic fever. Flavivirus infections are endemic to all continents except Antarctica. These viruses infect more than 200 million people and result in more than 100,000 fatalities per year. Although effective vaccines exist for YFV, JEV, and TBEV the difficulty of vaccinating large at-risk populations and the danger of adverse vaccination effects highlight the importance of developing antiviral therapeutics for treatment of severe flavivirus infections. The flavivirus methyltransferase has become an attractive target for such therapeutic interventions. The flavivirus MTase, encoded by the NS5 gene, functions similarly to many other MTases to transfer a methyl group from its cellular cofactor molecule, S-adenosyl-methionine, first to the guanine-N-7 and then the ribose of the flavivirus mRNA cap, with S-adenosyl homocysteine formed as a by-product in both steps.
