Synthesis and biological evaluation of novel podophyllotoxin-NSAIDs conjugates as multifunctional anti-MDR agents against resistant human hepatocellular carcinoma Bel-7402/5-FU cells

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 conjuga...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2017-05, Vol.131, p.81-91
Main Authors: Zhang, Lei, Liu, Lai, Zheng, Chengyue, Wang, Yang, Nie, Xuqiang, Shi, Dabin, Chen, Yongzheng, Wei, Gang, Wang, Jing
Format: Article
Language:English
Subjects:
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Anti-MDR activity
Apoptosis - drug effects
Bel-7402/5-FU
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - pathology
Cell Cycle - drug effects
Cell Line
Conjugate
Dose-Response Relationship, Drug
Drug Resistance, Multiple - drug effects
Drug Resistance, Neoplasm - drug effects
Humans
Liver Neoplasms - drug therapy
Liver Neoplasms - pathology
Molecular Structure
NSAIDs
Podophyllotoxin
Podophyllotoxin - chemistry
Podophyllotoxin - pharmacology
Structure-Activity Relationship
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Summary: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. [Display omitted] •Novel podophyllotoxin-NSAIDs conjugates were synthesized.•Conjugate A1 displayed an significant IC50 value of 0.065 ± 0.016 μM against Bel-7402/5-FU cells.•Conjugates triggered cell cycle arrest, induced apoptosis, disrupted microtubule and showed antimigratory activity.•Conjugates regulated levels of cell cycle arrest-, apoptosis-, migratory-, inflammatory- and MDR- related proteins.•Conjugates modulated ERK1/2, STAT3 and AKT signaling.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2017.03.011