Synthesis of Flavokawain Analogues and their Anti-neoplastic Effects on Drug-resistant Cancer Cells Through Hsp90 Inhibition

摘要

Hsp90 is an ubiquitous molecular chaperone protein, which plays an important role in regulating maturation and stabilization of many oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 represents great promise as a therapeutic target of cancer. In this study, we synthesized flavokawain analogues and evaluated their biological activities against drug-resistant cancer cells. The study indicated that compound li impaired the growth of gefitinib-resistant non-small cell lung cancer (H1975), down-regulated the expression of Hsp90 client proteins including EGFR, Her2, Met, Akt and Cdk4, and up-regulated the expression of Hsp70. The result strongly suggested that compound li inhibited the proliferation of cancer cells through Hsp90 inhibition. Overall, compound li could serve as a potential lead compound to overcome the drag resistance in cancer chemotherapy.