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Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance

SIMPLE SUMMARY: Amino acid metabolism is aberrantly altered in pancreatic cancer (PC). Evidence suggests that circulating histidine (His) levels are low in PC. However, the role of His in modulating the progression of PC remains unknown. We determined the role of His in altering the therapeutic effe...

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Autores principales: Kumar, Narendra, Rachagani, Satyanarayana, Natarajan, Gopalakrishnan, Crook, Alexandra, Gopal, Thiyagarajan, Rajamanickam, Vinothkumar, Kaushal, Jyoti B., Nagabhishek, Sirpu N., Powers, Robert, Batra, Surinder K., Saraswathi, Viswanathan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177467/
https://www.ncbi.nlm.nih.gov/pubmed/37174059
http://dx.doi.org/10.3390/cancers15092593
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author Kumar, Narendra
Rachagani, Satyanarayana
Natarajan, Gopalakrishnan
Crook, Alexandra
Gopal, Thiyagarajan
Rajamanickam, Vinothkumar
Kaushal, Jyoti B.
Nagabhishek, Sirpu N.
Powers, Robert
Batra, Surinder K.
Saraswathi, Viswanathan
author_facet Kumar, Narendra
Rachagani, Satyanarayana
Natarajan, Gopalakrishnan
Crook, Alexandra
Gopal, Thiyagarajan
Rajamanickam, Vinothkumar
Kaushal, Jyoti B.
Nagabhishek, Sirpu N.
Powers, Robert
Batra, Surinder K.
Saraswathi, Viswanathan
author_sort Kumar, Narendra
collection PubMed
description SIMPLE SUMMARY: Amino acid metabolism is aberrantly altered in pancreatic cancer (PC). Evidence suggests that circulating histidine (His) levels are low in PC. However, the role of His in modulating the progression of PC remains unknown. We determined the role of His in altering the therapeutic effectiveness of gemcitabine (Gem) against PC. We provide evidence that the expression of histidine ammonia lyase (HAL), an enzyme involved in His catabolism, is greatly increased in mouse and human pancreatic tumors. We show that combining His with Gem led to enhanced cytotoxic effects against aggressive PC cell lines. Our metabolomics analysis revealed that His treatment results in the depletion of amino acids supporting glutathione production. His depletes cellular glutathione and increased hydrogen peroxide production, indicating that His potentiates the cytotoxic effects of Gem by promoting oxidative stress. A combination of His and Gem was effective in attenuating pancreatic tumor growth and improving the survival of mice exhibiting xenograft tumors. Our findings suggest that His supplementation is an effective nutritional approach to enhance the efficacy of chemotherapeutic drugs. ABSTRACT: Due to the severe toxicity posed by chemotherapeutic drugs, adjuvant nutritional intervention has gained increased attention in the treatment of pancreatic cancer (PC). Amino acid (AA) metabolism is aberrantly regulated in PC and circulating histidine (His) levels are low in PC patients. We hypothesized that His uptake and/or metabolism is dysregulated in PC and that combining His with gemcitabine (Gem), a drug used in the treatment of PC, will enhance the anti-cancer effects of Gem. We performed in vitro and in vivo studies to determine the anticancer effect of the combination of His and Gem against lethal PC. We demonstrate that circulating His levels are low in both human subjects and genetically engineered mice exhibiting pancreatic tumors. Interestingly, the expression of histidine ammonia lyase, an enzyme involved in His catabolism, is higher in PC compared to normal subjects. His + Gem exerts a more potent cytotoxic effect in PC cells compared to individual treatments. His treatment results in a profound increase in His accumulation, accompanied by a depletion of a number of AAs, promoting cancer cell survival and/or glutathione (GSH) synthesis. His but not Gem increases hydrogen peroxide and depletes cellular GSH. Supplementation with GSH protects cells against His + Gem-induced cytotoxicity. Further, our in vivo studies demonstrate that His + Gem potently reduced tumor mass and improved mouse survival. Taken together, our data suggest that PC cells exhibit an aberrant His uptake/accumulation which, in turn, leads to oxidative stress and depletion of AA pool, thereby enhancing the anticancer effect of Gem.
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spelling pubmed-101774672023-05-13 Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance Kumar, Narendra Rachagani, Satyanarayana Natarajan, Gopalakrishnan Crook, Alexandra Gopal, Thiyagarajan Rajamanickam, Vinothkumar Kaushal, Jyoti B. Nagabhishek, Sirpu N. Powers, Robert Batra, Surinder K. Saraswathi, Viswanathan Cancers (Basel) Article SIMPLE SUMMARY: Amino acid metabolism is aberrantly altered in pancreatic cancer (PC). Evidence suggests that circulating histidine (His) levels are low in PC. However, the role of His in modulating the progression of PC remains unknown. We determined the role of His in altering the therapeutic effectiveness of gemcitabine (Gem) against PC. We provide evidence that the expression of histidine ammonia lyase (HAL), an enzyme involved in His catabolism, is greatly increased in mouse and human pancreatic tumors. We show that combining His with Gem led to enhanced cytotoxic effects against aggressive PC cell lines. Our metabolomics analysis revealed that His treatment results in the depletion of amino acids supporting glutathione production. His depletes cellular glutathione and increased hydrogen peroxide production, indicating that His potentiates the cytotoxic effects of Gem by promoting oxidative stress. A combination of His and Gem was effective in attenuating pancreatic tumor growth and improving the survival of mice exhibiting xenograft tumors. Our findings suggest that His supplementation is an effective nutritional approach to enhance the efficacy of chemotherapeutic drugs. ABSTRACT: Due to the severe toxicity posed by chemotherapeutic drugs, adjuvant nutritional intervention has gained increased attention in the treatment of pancreatic cancer (PC). Amino acid (AA) metabolism is aberrantly regulated in PC and circulating histidine (His) levels are low in PC patients. We hypothesized that His uptake and/or metabolism is dysregulated in PC and that combining His with gemcitabine (Gem), a drug used in the treatment of PC, will enhance the anti-cancer effects of Gem. We performed in vitro and in vivo studies to determine the anticancer effect of the combination of His and Gem against lethal PC. We demonstrate that circulating His levels are low in both human subjects and genetically engineered mice exhibiting pancreatic tumors. Interestingly, the expression of histidine ammonia lyase, an enzyme involved in His catabolism, is higher in PC compared to normal subjects. His + Gem exerts a more potent cytotoxic effect in PC cells compared to individual treatments. His treatment results in a profound increase in His accumulation, accompanied by a depletion of a number of AAs, promoting cancer cell survival and/or glutathione (GSH) synthesis. His but not Gem increases hydrogen peroxide and depletes cellular GSH. Supplementation with GSH protects cells against His + Gem-induced cytotoxicity. Further, our in vivo studies demonstrate that His + Gem potently reduced tumor mass and improved mouse survival. Taken together, our data suggest that PC cells exhibit an aberrant His uptake/accumulation which, in turn, leads to oxidative stress and depletion of AA pool, thereby enhancing the anticancer effect of Gem. MDPI 2023-05-03 /pmc/articles/PMC10177467/ /pubmed/37174059 http://dx.doi.org/10.3390/cancers15092593 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kumar, Narendra
Rachagani, Satyanarayana
Natarajan, Gopalakrishnan
Crook, Alexandra
Gopal, Thiyagarajan
Rajamanickam, Vinothkumar
Kaushal, Jyoti B.
Nagabhishek, Sirpu N.
Powers, Robert
Batra, Surinder K.
Saraswathi, Viswanathan
Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance
title Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance
title_full Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance
title_fullStr Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance
title_full_unstemmed Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance
title_short Histidine Enhances the Anticancer Effect of Gemcitabine against Pancreatic Cancer via Disruption of Amino Acid Homeostasis and Oxidant—Antioxidant Balance
title_sort histidine enhances the anticancer effect of gemcitabine against pancreatic cancer via disruption of amino acid homeostasis and oxidant—antioxidant balance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177467/
https://www.ncbi.nlm.nih.gov/pubmed/37174059
http://dx.doi.org/10.3390/cancers15092593
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