Human uridine phosphorylase-1 inhibitors: a new approach to ameliorate 5-fluorouracil-induced intestinal mucositis

Renck, Daiana; Santos, André A.; Machado, Pablo; Petersen, Guilherme Oliveira; Lopes, Tiago Giuliani; Santos, Daniel Silas Veras dos; Campos, Maria M.; Basso, Luiz Augusto

doi:10.1007/s10637-014-0135-0

Cited by 12 publications

(9 citation statements)

References 20 publications

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“…The selected regimen of 5-fluorouracil renal injury is based on previous reports [24-26] and our preliminary results. The selected doses for Camel milk are consistent with previous studies [13, 14, 16] and the dose of the reference antioxidant Quercetin is in line with previous literature [6].…”

Section: Methodsmentioning

confidence: 99%

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

Arab

Salama

Maghrabi

2018

Cell Physiol Biochem

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Background/Aims: The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats. Methods: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting. Results: CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use. Conclusion: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K/Akt/eNOS pathway.

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Section: Methodsmentioning

confidence: 99%

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

Arab

Salama

Maghrabi

2018

Cell Physiol Biochem

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“…Allopurinol and uridine were shown to be effective in reducing 5-fluorouracil oral toxicity in preclinical studies (110–114). Despite these results, they were ineffective approaches in randomized clinical trials as a therapy to reduce the treatment-related oral toxicity (115, 116).…”

Section: Symptomatic Treatment Of Riommentioning

confidence: 99%

Radiation-Induced Oral Mucositis

2017

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Radiation-induced oral mucositis (RIOM) is a major dose-limiting toxicity in head and neck cancer patients. It is a normal tissue injury caused by radiation/radiotherapy (RT), which has marked adverse effects on patient quality of life and cancer therapy continuity. It is a challenge for radiation oncologists since it leads to cancer therapy interruption, poor local tumor control, and changes in dose fractionation. RIOM occurs in 100% of altered fractionation radiotherapy head and neck cancer patients. In the United Sates, its economic cost was estimated to reach 17,000.00 USD per patient with head and neck cancers. This review will discuss RIOM definition, epidemiology, impact and side effects, pathogenesis, scoring scales, diagnosis, differential diagnosis, prevention, and treatment.

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“…Several drug candidates capable of increasing the concentration of uridine to support synergetic treatment of 5-FU, including 5-benzylacyclouridine (BAU) and 5-(phenylthio)acyclouridine (PTAU), have been developed. 25,[47][48][49][50] However, the mechanism of uridine rescue remains unclear. One possible explanation, based on the Le Chatelier principle, is that the increased level of uridine decreases the conversion of 5-FU to 5-fluoriuridine.…”

Section: Metabolites May Alter the Function Of Proteins In Cancer Cmentioning

confidence: 99%

“…[20][21][22][23] It is known that the expression level of hUP1 is usually increased in cancer cells, possibly because mutations in the tumor-suppressor protein, p53, which are common in cancer, abolish p53-mediated inhibition of hUP1 gene transcription. The high level of hUP1 in cancer cells has been exploited in the development of 5-fluorouracil (5-FU)-based chemotherapy for the treatment of various cancers, 24,25 reflecting the fact that hUP1 is the primary contributor to activation of 5-FU to produce 5-fluorouridine. This abnormal nucleotide can then be incorporated into newly synthesized RNA, resulting in destabilization of the conformation of newly synthesized RNA and disruption of its function, ultimately causing the death of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Metabolites modulate the functional state of human uridine phosphorylase I

et al. 2020

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Metabolic pathways in cancer cells typically become reprogrammed to support unconstrained proliferation. These abnormal metabolic states are often accompanied by accumulation of high concentrations of ATP in the cytosol, a phenomenon known as the Warburg Effect. However, how high concentrations of ATP relate to the functional state of proteins is poorly understood. Here, we comprehensively studied the influence of ATP levels on the functional state of the human enzyme, uridine phosphorylase I (hUP1), which is responsible for activating the chemotherapeutic pro-drug, 5-fluorouracil. We found that elevated levels of ATP decrease the stability of hUP1, leading to the loss of its proper folding and function. We further showed that the concentration of hUP1 exerts a critical influence on this ATP-induced destabilizing effect. In addition, we found that ATP interacts with hUP1 through a partially unfolded state and accelerates the rate of hUP1 unfolding. Interestingly, some structurally similar metabolites showed similar destabilization effects on hUP1. Our findings suggest that metabolites can alter the folding and function of a human protein, hUP1, through protein destabilization. This phenomenon may be relevant in studying the functions of proteins that exist in the specific metabolic environment of a cancer cell.

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Human uridine phosphorylase-1 inhibitors: a new approach to ameliorate 5-fluorouracil-induced intestinal mucositis

Abstract: Our results bring support to the hUP1 inhibitor strategy as a novel possibility of prevention and treatment of mucositis during the 5-FU chemotherapy, based on the approach of uridine accumulation in plasma and tissues.

Cited by 12 publications

References 20 publications

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

Radiation-Induced Oral Mucositis

Metabolites modulate the functional state of human uridine phosphorylase I

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