Inhibition of glucose-6-phosphate dehydrogenase sensitizes cisplatin-resistant cells to death

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// Daniela Catanzaro 1 , Edoardo Gaude 2 , Genny Orso 3 , Carla Giordano 4 , Giulia Guzzo 5 , Andrea Rasola 5 , Eugenio Ragazzi 1 , Laura Caparrotta 1 , Christian Frezza 2 , Monica Montopoli 1 1 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy 2 MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK 3 IRCCS “E. Medea”, Conegliano, Italy 4 Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Roma, Italy 5 Department of Biomedical Sciences, University of Padova, Padova, Italy Correspondence to: Christian Frezza, e-mail: cf366@mrc-cu.cam.ac.uk Monica Montopoli, e-mail: monica.montopoli@unipd.it Keywords: cisplatin, drug resistance, cancer metabolism, PPP, transmitochondrial hybrids Received: March 22, 2015      Accepted: August 07, 2015      Published: August 17, 2015 ABSTRACT The mechanisms of cisplatin resistance, one of the major limitations of current chemotherapy, has only partially been described. We previously demonstrated that cisplatin-resistant ovarian cancer cells (C13), are characterized by reduced mitochondrial activity and higher glucose-dependency when compared to the cisplatin-sensitive counterpart (2008). In this work we further characterized the role of metabolic transformation in cisplatin resistance. By using transmitochondrial hybrids we show that metabolic reprogramming of cisplatin-resistant cell is not caused by inherent mtDNA mutations. We also found that C13 cells not only present an increased glucose-uptake and consumption, but also exhibit increased expression and enzymatic activity of the Pentose Phosphate pathway (PPP) enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH). Moreover, we show that cisplatin-resistant cells are more sensitive to G6PDH inhibition. Even if the metabolomic fingerprint of ovarian cancer cells remains to be further elucidated, these findings indicate that PPP offers innovative potential targets to overcome cisplatin resistance.