Cai Aimin, Zheng Hailun, Chen Zhiwei, Lin Xinlu, Li Chen, Yao Qing, Bhutia Yangzom D, Ganapathy Vadivel, Chen Ruijie, Kou Longfa
Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
Wenzhou Municipal Key Laboratory of Paediatric Pharmacy, Wenzhou 325027, China.
Biochem J. 2020 May 29;477(10):1923-1937. doi: 10.1042/BCJ20200275.
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.
吉西他滨是胰腺癌的一线化疗药物。为克服常见的吉西他滨耐药性，其他药物会与吉西他滨联合使用。众所周知，癌细胞会对细胞代谢进行重编程，同时上调选择性营养转运蛋白以供应改变后的代谢途径。我们之前的研究表明，氨基酸转运蛋白SLC6A14在胰腺癌中显著上调，且是一个可行的治疗靶点。α-甲基色氨酸（α-MT）是SLC6A14的阻断剂，在体外和体内对胰腺癌均有效。在本研究中，我们检验了α-MT可与吉西他滨协同治疗胰腺癌的假设。我们研究了α-MT与吉西他滨联合使用对人胰腺癌细胞系增殖、迁移和凋亡的影响，并使用基于1H-NMR的代谢组学分析研究其潜在机制。这些研究分别检测了细胞内代谢物谱和细胞外代谢物谱。α-MT与吉西他滨联合使用引发了多种代谢途径的显著变化，尤其是氨基酸代谢，涉及色氨酸、支链氨基酸、酮体和膜磷脂的途径有明显改变。未处理的对照细胞以及用吉西他滨或α-MT处理的细胞的代谢组学谱明显可区分，联合用药方案在一定程度上与单独使用α-MT和吉西他滨的组有重叠。这是第一项详细阐述吉西他滨、α-MT及其联合用药抗癌疗效代谢组学基础的研究。
