title: Synthesis and biological evaluation of novel podophyllotoxin-NSAIDs conjugates as multifunctional anti-MDR agents against resistant human hepatocellular carcinoma Bel-7402/5-FU cells.
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 IC50value 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.
authors.affiliation: School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China. Electronic address: lzhang@zmc.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China.
authors.forename: Lai
authors.initials: L
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China.
authors.forename: Chengyue
authors.initials: C
authors.lastname: Zheng
authors.affiliation: School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China.
authors.forename: Xuqiang
authors.initials: X
authors.lastname: Nie
authors.affiliation: School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China.
authors.forename: Dabin
authors.initials: D
authors.lastname: Shi
authors.affiliation: School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China.
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: CSIRO Manufacturing Flagship, PO Box 218, Lindfield, NSW 2070, Australia.
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.affiliation: School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China. Electronic address: wangjing@zmc.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011034:Podophyllotoxin
keywords: Anti-MDR activity; Bel-7402/5-FU; Conjugate; NSAIDs; Podophyllotoxin