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Insights into gemcitabine resistance and the potential for therapeutic monitoring.

ABSTRACT: INTRODUCTION:Gemcitabine is an important component of pancreatic cancer clinical management. Unfortunately, acquired gemcitabine resistance is widespread and there are limitations to predicting and monitoring therapeutic outcomes. OBJECTIVE:To investigate the potential of metabolomics to differentiate pancreatic cancer cells that develops resistance or respond to gemcitabine treatment. RESULTS:We applied 1D 1H and 2D 1H-13C HSQC NMR methods to profile the metabolic signature of pancreatic cancer cells. 13C6-glucose labeling identified 30 key metabolites uniquely altered between wild-type and gemcitabine-resistant cells upon gemcitabine treatment. Gemcitabine resistance was observed to reprogram glucose metabolism and to enhance the pyrimidine synthesis pathway. Myo-inositol, taurine, glycerophosphocholine and creatinine phosphate exhibited a "binary switch" in response to gemcitabine treatment and acquired resistance. CONCLUSION:Metabolic differences between naïve and resistant pancreatic cancer cells and, accordingly, their unique responses to gemcitabine treatment were revealed, which may be useful in the clinical setting for monitoring a patient's therapeutic response.

SUBMITTER: Gebregiworgis T

PROVIDER: S-EPMC6620022 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Insights into gemcitabine resistance and the potential for therapeutic monitoring.

Gebregiworgis Teklab T Bhinderwala Fatema F Purohit Vinee V Chaika Nina V NV Singh Pankaj K PK Powers Robert R

Metabolomics : Official journal of the Metabolomic Society 20181127 12

<h4>Introduction</h4>Gemcitabine is an important component of pancreatic cancer clinical management. Unfortunately, acquired gemcitabine resistance is widespread and there are limitations to predicting and monitoring therapeutic outcomes.<h4>Objective</h4>To investigate the potential of metabolomics to differentiate pancreatic cancer cells that develops resistance or respond to gemcitabine treatment.<h4>Results</h4>We applied 1D <sup>1</sup>H and 2D <sup>1</sup>H-<sup>13</sup>C HSQC NMR methods ...[more]

PMID: 30830412

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Project description:Hypertension poses a significant global health burden and is closely associated with cardiovascular morbidity. Pistacia lentiscus var. chia, commonly known as mastic, has emerged as a potential nutraceutical, due to its diverse pharmacological properties, including antioxidant and vasodilatory effects. Yet, its impact on hypertension in translational in vivo models and on hypertension-associated abnormalities in circulation, vasculature and kidneys have not been investigated. Herein we sought to decipher the putative antihypertensive potential of mastic, focusing on vascular and renal endothelium in clinically relevant in vivo models of essential hypertension. Two translational in vivo models of hypertension induced by Angiotensin II and Deoxycorticosterone acetate (DOCA)-High Salt in male rats, were utilized. Mastic administration at a therapeutic dose (220mg/kg, per os) was administered daily for four weeks, after the establishment of hypertension. Non-invasive blood pressure measurements and whole blood RNA sequencing and metabolomics were performed. Real-time PCR and Western blot analysis were conducted in kidney and aorta, to decipher its underlying antihypertensive mechanism. Mastic administration significantly reduced systolic, diastolic, and mean blood pressure in both in vivo hypertensive models. RNA sequencing revealed distinct gene expression profiles, with modulation of immune-related pathways in the Angiotensin II model and metabolic pathways in the DOCA-HS model. Additionally, RNA sequencing analysis revealed that mastic downregulated Rhob, Jun, Txnip and Egr1 mRNA expression in the circulation, paving towards a putative antioxidant and endothelial-targeted mechanism. Metabolomic analysis identified lysophosphatidylinositol upregulation as a consistent effect of mastic in both in vivo models, being implicated with improved endothelial homeostasis. RT-PCR analysis in the kidneys and aorta, showed that mastic increased endothelial markers such as Vegfa and Egr-1 mRNA expression in both experimental models. Concerning the endothelial homeostasis, mastic additionally increased renal nitric oxide synthase phosphorylation in both in vivo models of hypertension. This study highlights the potential of mastic as a natural adjuvant therapy for hypertension. The findings shed new light on its molecular mechanisms of action, providing insights into its protective impact on renal endothelium.

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Insights into gemcitabine resistance and the potential for therapeutic monitoring.

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Insights into gemcitabine resistance and the potential for therapeutic monitoring.

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