FM807, a curcumin analogue, shows potent antitumor effects in nasopharyngeal carcinoma cells by heat shock protein 90 inhibition.
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy usually associated with overexpression of both epidermal growth factor receptor (EGFR) and β-catenin. FM807 is a novel curcumin analogue with antitumor activity against both poorly and well-differentiated NPC cell lines as well as good selectivity for tumor cells. FM807 actions were shown to include inhibition of cell growth, induction of necrotic/late apoptotic cell death, and G1 arrest in NPC cells. Crucially, it exhibited potent antitumor effects both in vitro and in vivo. Binding of FM807 to the N-terminus of Hsp90 disrupted Hsp90/client complexes, resulting in degradation of the Hsp90 client protein EGFR and inhibition of the downstream Raf/MEK/ERK and PI3K/AKT pathway. FM807 also depleted levels of the intranuclear transcription factors β-catenin, Cyclin D1 and c-Myc levels by inhibiting Hsp90 chaperoned nuclear transport. In conjunction with its low toxicity in NPC xenograft mice, these results provide a sound preclinical basis for further development of FM807 as a novel therapeutic agent in the treatment of NPC.
School of Pharmacy, Fujian Medical University, Fuzhou 350004, China.|Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fuzhou 350004, China.
Min
M
Ye
School of Pharmacy, Fujian Medical University, Fuzhou 350004, China.
Wei
W
Huang
School of Pharmacy, Fujian Medical University, Fuzhou 350004, China.
Wen-Wei
WW
Wu
School of Pharmacy, Fujian Medical University, Fuzhou 350004, China.
Yang
Y
Liu
The First Affiliated Hospital of Fujian Medical University, Fuzhou 350004, China.
Sheng-Nan
SN
Ye
School of Pharmacy, Fujian Medical University, Fuzhou 350004, China.|Fuijan Provincial Key Laboratory of Natural Medicine Pharmacology, Fuzhou 350004, China.
Jian-Hua
JH
Xu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019938:Cyclin D1 / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C000622083:FM807; D018841:HSP90 Heat-Shock Proteins; D051176:beta Catenin; D019938:Cyclin D1; C512478:EGFR protein, human; D066246:ErbB Receptors; D003474:Curcumin
FM807; Hsp90 inhibitor; epidermal growth factor receptor; nasopharyngeal carcinoma; β-catenin