The isoprenoid derivative N6-benzyladenosine (CM223) exerts antitumor effect in glioma patient-derived primary cells through the mevalonate pathway

Abstract BACKGROUND AND PURPOSE: N6-Isopentenyladenosine (i6A) is a modified nucleoside exerting in vitro and in vivo antiproliferative effects. We previously demonstrated that the i6A action is correlated to farnesyl pyrophosphate synthase (FPPS) expression and activity, a key enzyme involved in the mevalonate (MVA) pathway, which is found aberrant in brain cancer. To develop new anti-glioma strategies, we looked for other valuable compounds exhibiting improved activity as compared to i6A. EXPERIMENTAL APPROACH: we designed and synthesized i6A derivatives characterized by the introduction of diverse chemical moieties in the N6 position of adenosine and tested for their efficacy in U87 and primary derived patient's glioma cell model. NMR based structural analysis, molecular docking calculations and siRNA mediated knock-down helped to clarify the molecular basis of their action, targeting FPPS protein. KEY RESULTS: We demonstrated that CM223, the i6A derivative including a benzyl moiety in N6 position of adenine, is endowed with a marked activity in selectively targeting glioma cells but not normal human astrocytes (NHA). This is achieved by the induction of intrinsic pathways of apoptosis and inhibition of proliferation along a FPPS-dependent protein prenylation blocking, which counteract the oncogenic signaling mediated by the epidermal growth factor receptor (EGFR). CONCLUSION AND IMPLICATIONS: This biological effect together with structural data on interaction of CM223 with FPPS, gain additional evidence on the correlation of the i6A/CM223 antitumoral activity with FPPS modulation. Because the MVA pathway is becoming an important promising target, CM223 and derivatives should be considered interesting active molecules in antiglioma pharmacological research.