Stilbene derivatives that are colchicine-site microtubule inhibitors have antileukemic activity and minimal systemic toxicity.
Stilbenes are a group of natural compounds with many biological activities. Two highly potent stilbenes, cis-3,4',5-trimethoxy-3'-aminostilbene (stilbene 5c) and cis-3,4',5-trimethoxy-3'-hydroxystilbene (stilbene 6c) induce G2/M cell-cycle arrest and leukemic cell death in nanomolarity range without affecting normal bone marrow progenitor cells. The mechanism of stilbenes is mediated by interfering with microtubule polymerization through the colchicine-binding site. Docking of the stilbenes into tubulin structure confirms that stilbenes fit into the colchicine-binding pocket. Animal studies show that stilbenes are well tolerated in mice and are capable of inducing more than 50% leukemic cell death by a single dose injection. A 5-day treatment with low-dose stilbenes suppresses tumor growth in mice with established tumor xenografts. No major organ damage was detected by histological section. Our results indicate that stilbene 5c is a microtubule-interfering agent and can be potentially useful in leukemic therapy.
Cao
Thai M
TM
Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
Durrant
David
D
Tripathi
Ashutosh
A
Liu
Jihua
J
Tsai
Schickwann
S
Kellogg
Glen E
GE
Simoni
Daniele
D
Lee
Ray M
RM
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D018920:Coculture Techniques; D003078:Colchicine / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000637:transplantation; D006367:HeLa Cells / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D008870:Microtubules / Q000187:drug effects*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D013267:Stilbenes / Q000737:chemistry* / Q000627:therapeutic use* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000187:drug effects; D050257:Tubulin Modulators / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D020298:U937 Cells / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; C529077:cis-3,4',5-trimethoxy-3'-aminostilbene; C529078:cis-3,4',5-trimethoxy-3'-hydroxystilbene; D019009:Proto-Oncogene Proteins c-kit; D003078:Colchicine