The isoprenoid derivative N6 -benzyladenosine CM223 exerts antitumor effects 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 actions of i6A correlate with the expression and activity of farnesyl pyrophosphate synthase (FPPS), a key enzyme involved in the mevalonate (MVA) pathway, which is aberrant in brain cancer. To develop new anti-glioma strategies, we tested related compounds exhibiting greater activity than 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 cells and in primary glioma cultures, derived from patients. NMR-based structural analysis, molecular docking calculations and siRNA mediated knockdown were used to clarify the molecular basis of their action, targeting FPPS protein.

KEY RESULTS:

CM223, the i6A derivative including a benzyl moiety in N6 position of adenine, showed marked activity in selectively targeting glioma cells, but not normal human astrocytes. This was due to induction of intrinsic pathways of apoptosis and inhibition of proliferation, along with blockade of FPPS-dependent protein prenylation, which counteracted oncogenic signalling mediated by EGF receptors.

CONCLUSION AND IMPLICATIONS:

The biological effects together with structural data on interaction of CM223 with FPPS, provided additional evidence for the correlation of the i6A/CM223 antitumor activity with FPPS modulation. Because the MVA pathway is an important promising target, CM223 and its derivatives should be considered interesting active molecules in antiglioma research.

• Authors: Elena Ciaglia, Manuela Grimaldi, Mario Abate, Mario Scrima, Manuela Rodriquez, Chiara Laezza, Roberta Ranieri, Simona Pisanti, Pierangela Ciuffreda, Clementina Manera, Patrizia Gazzerro, Anna Maria D'Ursi, Maurizio Bifulco
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 174 Issue 14 Pg. 2287-2301 (Jul 2017) ISSN: 1476-5381 [Electronic] England
• PMID: 28419419 (Publication Type: Journal Article)
• Copyright: © 2017 The British Pharmacological Society.

Chemical References

• Antineoplastic Agents
• Terpenes
• Adenosine
• Mevalonic Acid

Topics

• Adenosine (analogs & derivatives, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Glioma (drug therapy, metabolism, pathology)
• Humans
• Mevalonic Acid (metabolism)
• Models, Molecular
• Molecular Structure
• Structure-Activity Relationship
• Terpenes (chemical synthesis, chemistry, pharmacology)