Synthesis and biological evaluation of novel podophyllotoxin-NSAIDs conjugates as multifunctional anti-MDR agents against resistant human hepatocellular carcinoma Bel-7402/5-FU cells.
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| Abstract |
Currently, multi-drug resistance (MDR) to chemotherapy agents is a major hindrance to the treatment of hepatocellular carcinoma. Development of novel antineoplastic drug with anti-MDR activity is an effectively way to overcome cancer resistance. In present study, novel podophyllotoxin-NSAIDs conjugates were synthesized, and their antiproliferative activities were evaluated in vitro. The most potent conjugate, A1, displayed selective cytotoxicity against resistant Bel-7402/5-FU cells with an IC50 value of 0.065 ± 0.016 μM and a lower resistant factor value of 0.32. In addition, all conjugate molecules efficiently triggered cell cycle arrest at S + G2 phase, induced apoptosis, disrupted the microtubule network and showed antimigratory activity in Bel-7402/5-FU cells. Finally, three conjugates regulated the levels of cell cycle arrest-, apoptosis-, migratory-, inflammatory- and MDR-related proteins, as well as three signaling in Bel-7402/5-FU cells by some but not all similar molecular mechanisms. Together, these findings highlighted the cytotoxic and multifunctional anti-MDR properties of podophyllotoxin-NSAIDs conjugates for the first time, which may be promising candidates for intervention of resistant hepatocellular carcinoma.
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| Authors | Lei Zhang, Lai Liu, Chengyue Zheng, Yang Wang, Xuqiang Nie, Dabin Shi, Yongzheng Chen, Gang Wei, Jing Wang |
| Journal | European journal of medicinal chemistry (Eur J Med Chem) Vol. 131 Pg. 81-91 (May 05 2017) ISSN: 1768-3254 [Electronic] France |
| PMID | 28301815 (Publication Type: Journal Article) |
| Copyright | Copyright © 2017 Elsevier Masson SAS. All rights reserved. |
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