C1206, a novel curcumin derivative, potently inhibits Hsp90 and human chronic myeloid leukemia cells in vitro

Authors: Ying-juan FAN1,2, Yi-xiang ZHOU3, Lian-ru ZHANG4,5, Qiao-fa LIN1,2, Ping-zhang GAO6, Fang CAI1,2, Li-ping ZHU1,2, Bi LIU1,2, Jian-hua XU1,2
1 School of Pharmacy, Fujian Medical University, Fuzhou 350108, China
2 Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fuzhou 350108, China
3 Department of Pharmacy, Xiamen Xianyue Hospital, Xiamen 361012, China
4 School of Life
5 Science, Xiamen University, Xiamen 361005, China
6 College of Chemistry and Life Science, Quanzhou Normal University, Quanzhou 362000, China
Corresponding to: Ying-juan FAN:, Bi LIU:, Jian-hua XU:,
DOI: 10.1038/aps.2017.160
Received: 7 December 2017
Accepted: 1 May 2017
Advance online: 16 August 2017


4-(4-Pyridinyl methylene) curcumin (C1206) is a new derivative of curcumin that is more active than curcumin in inhibition of heat shock protein 90 (Hsp90) and antitumor action. In this study we investigated the relationship between C1206-induced inhibition of Hsp90 and its anti-leukemic effects. The fluorescence quenching experiments showed that C1206 seemed to bind the middle dimerization domain of Hsp90. The interaction between C1206 and Hsp90 was driven mainly by electrostatic interaction. In in vitro enzyme activity assay, C1206 dose-dependently inhibited Hsp90 ATPase activity with an IC50 value of 4.17 μmol/L. In both imatinibsensitive K562 chronic myeloid leukemia cells and imatinib-resistant K562/G01 chronic myeloid leukemia cells, C1206 (0.4–3.2 μmol/L) dose-dependently caused the degradation of Hsp90 client proteins and downstream proteins (AKT, MEK, ERK, C-RAF, P-AKT, P-MEK and P-ERK). Furthermore, C1206 (0.4–3.2 μmol/L) dose-dependently induced apoptosis of K562 and K562/G01 cells through triggering mitochondrial pathway. Consistent with this result, C1206 inhibited the proliferation of K562 and K562/G01 cells with IC50 values of 1.10 and 0.60 μmol/L, respectively. These results suggest that C1206 is a novel Hsp90 inhibitor and a promising therapeutic agent for chronic myeloid leukemia.
Keywords: curcumin derivative; Hsp90 inhibitor; anticancer drug; ATPase activity; apoptosis; mitochondria; chronic myeloid leukemia; K562 cells; K562/G01 cells