A new inhibitor of glucose-6-phospate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo

Mele, L., Paino, F., Papaccio, F., Regad, T. ORCID: 0000-0003-4028-6368, Boocock, D. ORCID: 0000-0002-7333-3549, Stiuso, P., Lombardi, A., Liccardo, D., Aquino, G., Barbieri, A., Arra, C., Coveney, C., La Noce, M., Papaccio, G., Caraglia, M., Tirino, V. and Desiderio, V., 2018. A new inhibitor of glucose-6-phospate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo. Cell Death & Disease, 9: 572. ISSN 2041-4889

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Abstract

Pentose Phosphate Pathway (PPP) is a major glucose metabolism pathway which has a fundamental role in cancer growth and metastasis. Even though PPP blockade has been pointed out as a very promising strategy against cancer, effective anti-PPP agents are not still available in the clinical setting. Here, we demonstrate that the natural molecule polydatin inhibits glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP. Polydatin blocks G6PD causing accumulation of reactive oxygen species and strong increase of endoplasmic reticulum stress. These effects are followed by cell cycle block in S phase, an about 50% of apoptosis, and 60% inhibition of invasion in vitro. Accordingly, in an orthotopic metastatic model of tongue cancer, 100 mg/kg polydatin induced an about 30% tumor size reduction with an about 80% inhibition of lymph node metastases and 50% reduction of lymph node size (p< 0.005). Polydatin is not toxic in animals up to a dose of 200 mg/kg and a phase II clinical trial shows that a is also well tolerated in humans (40 mg twice a day for 90 days). Thus, polydatin may be used as a reliable tool to limit human cancer growth and metastatic spread.

Item Type: Journal article
Alternative Title: Running title: Polydatin inhibits pentose phosphate pathway
Publication Title: Cell Death & Disease
Creators: Mele, L., Paino, F., Papaccio, F., Regad, T., Boocock, D., Stiuso, P., Lombardi, A., Liccardo, D., Aquino, G., Barbieri, A., Arra, C., Coveney, C., La Noce, M., Papaccio, G., Caraglia, M., Tirino, V. and Desiderio, V.
Publisher: Nature Publishing Group
Date: 2018
Volume: 9
ISSN: 2041-4889
Identifiers:
NumberType
10.1038/s41419-018-0635-5DOI
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 11 May 2018 13:32
Last Modified: 31 May 2018 09:50
URI: http://irep.ntu.ac.uk/id/eprint/33543

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