Withanolides-induced breast cancer cell death is correlated with their ability to inhibit heat protein 90.
Withanolides are a large group of steroidal lactones found in Solanaceae plants that exhibit potential anticancer activities. We have previously demonstrated that a withanolide, tubocapsenolide A, induced cycle arrest and apoptosis in human breast cancer cells, which was associated with the inhibition of heat shock protein 90 (Hsp90). To investigate whether other withanolides are also capable of inhibiting Hsp90 and to analyze the structure-activity relationships, nine withanolides with different structural properties were tested in human breast cancer cells MDA-MB-231 and MCF-7 in the present study. Our data show that the 2,3-unsaturated double bond-containing withanolides inhibited Hsp90 function, as evidenced by selective depletion of Hsp90 client proteins and induction of Hsp70. The inhibitory effect of the withanolides on Hsp90 chaperone activity was further confirmed using in vivo heat shock luciferase activity recovery assays. Importantly, Hsp90 inhibition by the withanolides was correlated with their ability to induce cancer cell death. In addition, the withanolides reduced constitutive NF-κB activation by depleting IκB kinase complex (IKK) through inhibition of Hsp90. In estrogen receptor (ER)-positive MCF-7 cells, the withanolides also reduced the expression of ER, and this may be partly due to Hsp90 inhibition. Taken together, our results suggest that Hsp90 inhibition is a general feature of cytotoxic withanolides and plays an important role in their anticancer activity.
Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan.
Hui-Chun
HC
Wang
Yi-Ling
YL
Tsai
Yang-Chang
YC
Wu
Fang-Rong
FR
Chang
Mei-Hsin
MH
Liu
Wen-Ying
WY
Chen
Chin-Chung
CC
Wu
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering; D013329:Structure-Activity Relationship; D054358:Withanolides / Q000737:chemistry / Q000494:pharmacology*
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D054358:Withanolides