Xu Qingwen, Liu Yuxi, Sun Wen, Song Tiantian, Jiang Xintong, Zeng Kui, Zeng Su, Chen Lu, Yu Lushan
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacology, Affiliated Hangzhou First Peoples Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China.
Cancers (Basel). 2022 May 22;14(10):2551. doi: 10.3390/cancers14102551.
Hypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatment.
肿瘤的缺氧微环境和代谢失调会削弱化疗药物的治疗效果，导致耐药性和肿瘤转移，这一直是包括肾细胞癌（RCC）在内的实体瘤治疗面临的挑战。在此，我们从评估RCC细胞中的甲硫氨酸代谢入手，证明了在缺氧条件下，RCC细胞中甲硫氨酸积累的增加是由L型氨基酸转运体1（LAT1）介导的。谷胱甘肽（GSH）作为甲硫氨酸的代谢产物，会通过化学螯合作用减弱奥沙利铂的治疗效果。在体外和体内，使用LAT1抑制剂JPH203减少甲硫氨酸摄取，通过降低GSH生成，显著增强了RCC细胞对奥沙利铂的敏感性。因此，我们提出了一种基于奥沙利铂和LAT1抑制剂联合使用的有效且稳定的治疗策略，有望在一定程度上解决RCC在缺氧条件下对铂类药物的耐药性问题，为新治疗策略的开发和RCC治疗提供有意义的见解。
