Nurcahyanti Agustina Dr, Wink Michael
Institute of Pharmacy and Molecular Biotechnology, Heidelberg University , Heidelberg , Germany.
PeerJ. 2016 Jan 7;4:e1542. doi: 10.7717/peerj.1542. eCollection 2016.
The non-protein amino acid L-canavanine (L-CAV), an antimetabolite of L-arginine (L-ARG), can alter the 3D conformation of proteins when incorporated into a protein instead of L-ARG. L-CAV inhibits the proliferation of some tumour cells. The deprivation of L-ARG in the culture medium enhances the response of cells to L-CAV. This study aimed to investigate the interaction of L-CAV in combination with the chemotherapeutic drugs, doxorubicin (DOX) or cisplatin (CIS), in cancer cells, especially in the absence of L-ARG. A combination method based on the median-effect principle and mass-action law was used. The following cancer cells were employed: HeLa and Caco-2 cells, overexpressing argininosuccinate synthase (ASS), pancreatic cells (MIA PaCa-2 and BxPC-3) and hepatocellular carcinoma cells (Hep G2 and SK-HEP-1), with down-regulated ASS. When constant and non-constant ratios of L-CAV were combined with DOX and CIS, a synergistic potentiation of cytotoxicity was recorded. Cells expressing high levels of ASS were more sensitive to the treatment as compared to the cells with reduced ASS levels. Overall, this study may provide a new approach to targeting some cancer cells with L-CAV in combination with DNA-targeting drugs such as DOX and CIS, especially those cells which overexpress ASS, such as human cervical and colorectal carcinoma cells.
非蛋白质氨基酸L-刀豆氨酸（L-CAV）是L-精氨酸（L-ARG）的一种抗代谢物，当它取代L-ARG掺入蛋白质时，可改变蛋白质的三维构象。L-CAV可抑制某些肿瘤细胞的增殖。培养基中L-ARG的缺乏会增强细胞对L-CAV的反应。本研究旨在探讨L-CAV与化疗药物阿霉素（DOX）或顺铂（CIS）联合作用于癌细胞的情况，尤其是在缺乏L-ARG的情况下。采用了基于中位效应原理和质量作用定律的联合方法。使用了以下癌细胞：过表达精氨酸琥珀酸合成酶（ASS）的HeLa和Caco-2细胞、胰腺细胞（MIA PaCa-2和BxPC-3）以及ASS表达下调的肝癌细胞（Hep G2和SK-HEP-1）。当L-CAV以恒定和非恒定比例与DOX和CIS联合时，记录到细胞毒性的协同增强作用。与ASS水平降低的细胞相比，表达高水平ASS的细胞对治疗更敏感。总体而言，本研究可能为用L-CAV联合DOX和CIS等靶向DNA的药物靶向某些癌细胞提供一种新方法，尤其是那些过表达ASS的细胞，如人宫颈癌和结肠癌细胞。
