Gemcitabine is the first-line chemotherapy for pancreatic cancer. To overcome the often-acquired gemcitabine resistance, other drugs are used in combination with gemcitabine. It is well-known that cancer cells reprogram cellular metabolism, coupled with the up-regulation of selective nutrient transporters to feed into the altered metabolic pathways. Our previous studies have demonstrated that the amino acid transporter SLC6A14 is markedly up-regulated in pancreatic cancer and that it is a viable therapeutic target. α-Methyltryptophan (α-MT) is a blocker of SLC6A14 and is effective against pancreatic cancer in vitro and in vivo. In the present study, we tested the hypothesis that α-MT could synergize with gemcitabine in the treatment of pancreatic cancer. We investigated the effects of combination of α-MT and gemcitabine on proliferation, migration, and apoptosis in a human pancreatic cancer cell line, and examined the underlying mechanisms using 1H-NMR-based metabolomic analysis. These studies examined the intracellular metabolite profile and the extracellular metabolite profile separately. Combination of α-MT with gemcitabine elicited marked changes in a wide variety of metabolic pathways, particularly amino acid metabolism with notable alterations in pathways involving tryptophan, branched-chain amino acids, ketone bodies, and membrane phospholipids. The metabolomic profiles of untreated control cells and cells treated with gemcitabine or α-MT were distinctly separable, and the combination regimen showed a certain extent of overlap with the individual α-MT and gemcitabine groups. This represents the first study detailing the metabolomic basis of the anticancer efficacy of gemcitabine, α-MT and their combination.
Skip Nav Destination
Article navigation
May 2020
-
Cover Image
Cover Image
The cover image shows high resolution of the 20 lowest energy structures of kringle 2 of human plasminogen to AGL55-NS88.2 (top) and KT155-SS1448 (bottom). To learn more about this, see the article by Qiu and colleagues (pp. 1613–1630). The image was provided by Francis J. Castellino.
Research Article|
May 29 2020
Synergism between SLC6A14 blockade and gemcitabine in pancreactic cancer: a 1H-NMR-based metabolomic study in pancreatic cancer cells
Aimin Cai;
Aimin Cai
*
1Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
2Wenzhou Municipal Key Laboratory of Paediatric Pharmacy, Wenzhou 325027, China
3Institute of Metabonomics and Medical NMR, Wenzhou Medical University, Wenzhou 325035, China
Search for other works by this author on:
Hailun Zheng;
Hailun Zheng
*
1Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
2Wenzhou Municipal Key Laboratory of Paediatric Pharmacy, Wenzhou 325027, China
Search for other works by this author on:
Zhiwei Chen;
Zhiwei Chen
*
1Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
2Wenzhou Municipal Key Laboratory of Paediatric Pharmacy, Wenzhou 325027, China
Search for other works by this author on:
Xinlu Lin;
Xinlu Lin
1Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
2Wenzhou Municipal Key Laboratory of Paediatric Pharmacy, Wenzhou 325027, China
Search for other works by this author on:
Chen Li;
Chen Li
3Institute of Metabonomics and Medical NMR, Wenzhou Medical University, Wenzhou 325035, China
4School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
Search for other works by this author on:
Qing yao;
Qing yao
4School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
Search for other works by this author on:
Yangzom D. Bhutia;
Yangzom D. Bhutia
5Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
Search for other works by this author on:
Vadivel Ganapathy
;
Vadivel Ganapathy
5Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A
Search for other works by this author on:
Ruijie Chen;
1Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
2Wenzhou Municipal Key Laboratory of Paediatric Pharmacy, Wenzhou 325027, China
Correspondence: Longfa Kou (klfpharm@163.com) or Ruijie Chen (crjpharm@163.com)
Search for other works by this author on:
Longfa Kou
1Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
2Wenzhou Municipal Key Laboratory of Paediatric Pharmacy, Wenzhou 325027, China
Correspondence: Longfa Kou (klfpharm@163.com) or Ruijie Chen (crjpharm@163.com)
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
April 07 2020
Revision Received:
May 04 2020
Accepted:
May 07 2020
Accepted Manuscript online:
May 07 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (10): 1923–1937.
Article history
Received:
April 07 2020
Revision Received:
May 04 2020
Accepted:
May 07 2020
Accepted Manuscript online:
May 07 2020
Citation
Aimin Cai, Hailun Zheng, Zhiwei Chen, Xinlu Lin, Chen Li, Qing yao, Yangzom D. Bhutia, Vadivel Ganapathy, Ruijie Chen, Longfa Kou; Synergism between SLC6A14 blockade and gemcitabine in pancreactic cancer: a 1H-NMR-based metabolomic study in pancreatic cancer cells. Biochem J 29 May 2020; 477 (10): 1923–1937. doi: https://doi.org/10.1042/BCJ20200275
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.