https://scholars.lib.ntu.edu.tw/handle/123456789/383363
Title: | Intracellular delivery of recombinant arginine deiminase (rADI) by heparin-binding hemagglutinin adhesion peptide restores sensitivity in rADI-resistant cancer cells | Authors: | LI-JIUAN SHEN Wu, Fe-Lin Lin FE-LIN LIN WU Yeh, Tzyy-Harn Chen, Ying-Luen Chiu, Yu-Chin Cheng, Ju-Chen Wei, Ming-Feng Shen, Li-Jiuan |
Keywords: | cancer; HBHA; heparin-binding hemagglutinin adhesion; intracellular delivery; rADI; recombinant arginine deiminase; resistance | Issue Date: | 2014 | Journal Volume: | 11 | Journal Issue: | 8 | Start page/Pages: | 2777-2786 | Source: | Molecular Pharmaceutics | Abstract: | Recombinant arginine deiminase (rADI) has been used in clinical trials for arginine-auxotrophic cancers. However, the emergence of rADI resistance, due to the overexpression of argininosuccinate synthetase (AS), has introduced an obstacle in its clinical application. Here, we have proposed a strategy for the intracellular delivery of rADI, which depletes both extracellular and intracellular arginine, to restore the sensitivity of rADI-resistant cancer cells. In this study, the C terminus of heparin-binding hemagglutinin adhesion protein from Mycobacterium tuberculosis (HBHAc), which contains 23 amino acids, was used to deliver rADI into rADI-resistant human breast adenocarcinoma cells (MCF-7). Chemical conjugates (l- and d-HBHAc-SPDP-rADI) and a recombinant fusion protein (rHBHAc-ADI) were produced. l- and d-HBHAc-SPDP-rADI showed a significantly higher cellular uptake of rADI by MCF-7 cells compared to that of rADI alone. Cell viability was significantly decreased in a dose-dependent manner in response to l- and d-HBHAc-SPDP-rADI treatments. In addition, the ratio of intracellular concentration of citrulline to arginine in cells treated with l- and d-HBHAc-SPDP-rADI was significantly increased by 1.4- and 1.7-fold, respectively, compared with that obtained in cells treated with rADI alone (p < 0.001). Similar results were obtained with the recombinant fusion protein rHBHAc-ADI. Our study demonstrates that the increased cellular uptake of rADI by HBHAc modification can restore the sensitivity of rADI treatment in MCF-7 cells. rHBHAc-ADI may represent a novel class of antitumor enzyme with an intracellular mechanism that is independent of AS expression. ? 2014 American Chemical Society. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84905459957&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/383363 |
DOI: | 10.1021/mp5001372 | SDG/Keyword: | amino acid; arginine; arginine deiminase; citrulline; hemagglutinin; heparin binding hemagglutinin adhesion peptide; heparin binding protein; hybrid protein; unclassified drug; arginine deiminase; argininosuccinate synthase; citrulline; fluorescein; heparin-binding hemagglutinin; hybrid protein; hydrolase; lectin; peptide; article; breast adenocarcinoma; cancer cell; cancer resistance; cell viability; concentration (parameters); conjugate; controlled study; human; human cell; MCF 7 cell line; Mycobacterium tuberculosis; priority journal; synthesis; cell survival; chemistry; cytoplasm; dose response; drug delivery system; drug effects; drug resistance; endocytosis; metabolism; Neoplasms; tumor cell line; Amino Acids; Argininosuccinate Synthase; Cell Line, Tumor; Cell Survival; Citrulline; Cytoplasm; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Resistance, Neoplasm; Endocytosis; Fluorescein; Humans; Hydrolases; Lectins; MCF-7 Cells; Mycobacterium tuberculosis; Neoplasms; Peptides; Recombinant Fusion Proteins |
Appears in Collections: | 藥學系 |
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