Inhibition of pyruvate dehydrogenase kinase influence microbiota and metabolomic profile in pancreatic cancer xenograft
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RESEARCH NOTE
Inhibition of pyruvate dehydrogenase kinase influence microbiota and metabolomic profile in pancreatic cancer xenograft mice Kaarel Adamberg1,2, Raivo Vilu2,3 and Valerio Pazienza4*
Abstract Objective: Despite recent advances in treatment options, pancreatic cancer remains the most deadly major cancer. Targeting metabolism represents an emerging anti-cancer strategy. Results: Metagenomic 16S analysis was employed to explore the effect of Dichloroacetate (DCA) on the composition of the fecal microbiota and metabolomic profile was assessed on in vivo pancreatic cancer mouse xenograft model. Pancreatic cancer xenograft mice displayed a shift of microbiota’ profile as compared to control mice without DCA treatment and a significant decrease of the purine bases inosine xanthine together with their metabolicallyrelated compound hypoxanthine were observed in the DCA treated group as compared to the control group. Two aminoacids methionine and aspartic acid resulted decreased and increased respectively. DCA affects tumor environment and studies are needed in order to understand whether DCA supplementation could be supportive as synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients. Keywords: Pancreatic cancer, Microbiota, Metabolomic Introduction Pancreatic cancer (PC) is one of the most aggressive and highly lethal tumor ranked as the fourth leading cause of cancer-related deaths worldwide and it is expected to become the second leading cause of cancer death in the next decade. Despite recent advances in treatment options, pancreatic cancer has the worst survival rate of any organ site, with a median survival of less than six months and a 5-year survival rate of less than 5% [1]. Due to the lack of early symptoms and biomarkers that can predict the onset of PC, the latter is often not diagnosed until it is advanced and therefore is habitually referred to as a “silent killer”. The available therapeutic strategies based on surgery and conventional chemotherapy are still *Correspondence: [email protected] 4 Gastroenterology Unit I.R.C.C.S. “Casa Sollievo Della Sofferenza” Hospital, viale dei Cappuccini n.1, 71013 San Giovanni Rotondo, FG, Italy Full list of author information is available at the end of the article
essentially insufficient. Since metabolic reprogramming contributes to tumor development, targeting identified metabolic targets might represent a promising effective approach to treat pancreatic cancer, overcome chemoresistance and ameliorate patient’s prognosis and survival [2]. It is well known that tumor cells rely on glucose and glycolysis as a major source of energy [3] hence there is also a growing interest in fasting or calories restriction to prevent or treat cancer [4, 5]. It was previously demonstrated that rewiring carbohydrates metabolism differentially affects survival of pancreatic cancer cell lines [3] or retard pancreatic cancer tumor growth in pancreatic cancer in vivo model [6]. Pyruvat
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