Synthesis and biological evaluation of novel podophyllotoxin-NSAIDs conjugates as multifunctional anti-MDR agents against resistant human hepatocellular carcinoma Bel-7402/5-FU cells
- Eur J Med Chem. 2017 May 5:131:81-91. doi: 10.1016/j.ejmech.2017.03.011.
- 1. School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China. Electronic address: [email protected].
- 2. School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China.
- 3. CSIRO Manufacturing Flagship, PO Box 218, Lindfield, NSW 2070, Australia.
- 4. School of Pharmacy, Zunyi Medical University, Zunyi 563003, PR China. Electronic address: [email protected].
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.