Minimal Concentrations of a Chemically Modified Triterpene Derivative of  Ursolic Acid (UA) Rapidly Exterminate MDR HR-NB HTLA Cells, Outperforming UA and Etoposide 

Late-stage metastatic high-risk neuroblastoma (HR-NB) childhood cancer has < 50% survival rates, due to the emergence of resistance to available therapies, generally based on etoposide (ETO), doxorubicin (DOX), etc. Aiming at ameliorating this worrying scenario, 7 triterpenoid derivatives (1-7) were synthesized, decorating betulin (BET), betulinic acid (BA) and ursolic acid (UA). They were essayed on sensitive MYCN-amplified HTLA 230 cells and multidrug resistant (MDR) HTLA ER counterpart, known to be the most aggressive forms of HR-NB, regardless their phenotype. All compounds displayed from moderate to potent anticancer effects, but the anticancer potency of UA derivative 7, was exceptional. Specifically, 7 demonstrated potent activity against both cell lines (IC₅₀ = 1.75-0.58 vs. HTLA 230 and 4.30-2.90 µM vs. HTLA ER), eliciting up to sub micromolar concentrations, in 72h experiments. UA derivative 7 was superior to UA by 25.3-60.5- (HTLA 230) and 8.6-9.4-time (HTLA ER), and outperformed both UA and ETO already in 24h treatments by 8.4-58.9-fold (UA) and by 83.1-118.8-fold (ETO). Since, these incomparable discoveries recognised 7 as worthy of further experiments, clonogenicity tests, kinases phosphorylation investigations were performed. Clonogenicity was fully suppressed at all concentration tested in HTLA 230, while at the minimal concentration tested in HTLA ER, while kinase phosphorilation tests and the quantification of other markers evidenced that cytotoxicity of 7 was based on the inhibition of the AkT kinase system, due to the presence of acetylenic triple bond.