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Title:
A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo | Cell Death & Disease
Description:
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 it 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.
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headline:A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo
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headline:A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo
description: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, 100âmg/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 (pâ<â0.005). Polydatin is not toxic in animals up to a dose of 200âmg/kg and a phase II clinical trial shows that it is also well tolerated in humans (40âmg twice a day for 90 days). Thus, polydatin may be used as a reliable tool to limit human cancer growth and metastatic spread.
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url:http://orcid.org/0000-0002-4014-5306
affiliation:
name:University of Campania âLuigi Vanvitelliâ
address:
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
type:PostalAddress
type:Organization
email:[email protected]
name:Michele Caraglia
url:http://orcid.org/0000-0003-2408-6091
affiliation:
name:University of Campania âLuigi Vanvitelliâ
address:
name:Department of Biochemistry, Biophysics and General Pathology, University of Campania âLuigi Vanvitelliâ, Naples, Italy
type:PostalAddress
type:Organization
email:[email protected]
name:Virginia Tirino
affiliation:
name:University of Campania âLuigi Vanvitelliâ
address:
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
type:PostalAddress
type:Organization
name:Vincenzo Desiderio
url:http://orcid.org/0000-0003-1819-6083
affiliation:
name:University of Campania âLuigi Vanvitelliâ
address:
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
type:PostalAddress
type:Organization
PostalAddress:
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Oncologia Medica ed Ematologia, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale âF. Magrassi e A. Lanzaraâ, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
name:The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
name:Department of Biochemistry, Biophysics and General Pathology, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Department of Biochemistry, Biophysics and General Pathology, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Department of Research, Pathology Unit, Istituto Nazionale Tumori- IRCCS- Fondazione Pascale, Naples, Italy
name:SSD Sperimentazione Animale, Istituto Nazionale Tumori- IRCCS- Fondazione Pascale, Naples, Italy
name:SSD Sperimentazione Animale, Istituto Nazionale Tumori- IRCCS- Fondazione Pascale, Naples, Italy
name:The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Department of Biochemistry, Biophysics and General Pathology, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
name:Department of Experimental Medicine, University of Campania âLuigi Vanvitelliâ, Naples, Italy
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