Synergism between SLC6A14 blockade and gemcitabine in pancreactic cancer: a 1H-NMR-based metabolomic study in pancreatic cancer cells.

Abstract

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.

• Authors: Aimin Cai, Hailun Zheng, Zhiwei Chen, Xinlu Lin, Chen Li, Qing Yao, Yangzom D Bhutia, Vadivel Ganapathy, Ruijie Chen, Longfa Kou
• Journal: The Biochemical journal (Biochem J) Vol. 477 Issue 10 Pg. 1923-1937 (05 29 2020) ISSN: 1470-8728 [Electronic] England
• PMID: 32379301 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Amino Acid Transport Systems
• Amino Acids
• Antineoplastic Agents
• SLC6A14 protein, human
• Deoxycytidine
• alpha-methyltryptophan
• Tryptophan
• Gemcitabine

Topics

• Amino Acid Transport Systems (antagonists & inhibitors, metabolism)
• Amino Acids (drug effects, metabolism)
• Antineoplastic Agents
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Deoxycytidine (analogs & derivatives, therapeutic use)
• Drug Synergism
• Humans
• Metabolomics
• Pancreatic Neoplasms (drug therapy, pathology)
• Tryptophan (analogs & derivatives, metabolism, therapeutic use)
• Gemcitabine