In vitro and in vivo anticancer activities of synthetic (-)-laulimalide, a marine natural product microtubule stabilizing agent.
Laulimalide is a cytotoxic natural product isolated from marine sponges. It is structurally distinct from taxanes. However, like paclitaxel, laulimalide binds to tubulin and enhances microtubule assembly and stabilization. It exhibits potent inhibition of cellular proliferation with IC50 values in the low nM range against numerous cancer cell lines. In contrast to paclitaxel, however, laulimalide is also very potent against multidrug-resistant (MDR) cancer cell lines which overexpress P-glycoprotein (PgP). It has unique structural and biological properties, and attempts at synthesis have attracted considerable effort in recent years, resulting in more than ten published total syntheses. Despite this extensive attention, there have been no reported in vivo evaluations of laulimalide to date, probably due to the structural complexity of laulimalide and the scarcity of natural material. In our studies to explore the therapeutic potential of laulimalide, a total synthesis capable of producing gram quantities of laulimalide was designed, which enabled both in vitro and in vivo evaluation. Our in vitro results with synthetic material confirmed the previous reports that laulimalide is a mitotic blocker that can inhibit the growth of a variety of both non-MDR and MDR human cancer cell lines. However, despite demonstrating promise in cell-based and pharmacokinetic studies, laulimalide exhibited only minimal tumor growth inhibition in vivo and was accompanied by severe toxicity and mortality. The unfavorable efficacy to toxicity ratio in vivo suggests that laulimalide may have limited value for development as a new anticancer therapeutic agent.
Liu
Junke
J
Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA.
Towle
Murray J
MJ
Cheng
Hongsheng
H
Saxton
Philip
P
Reardon
Cathy
C
Wu
Jiayi
J
Murphy
Erin A
EA
Kuznetsov
Galina
G
Johannes
Charles W
CW
Tremblay
Martin R
MR
Zhao
Hongjuan
H
Pesant
Marc
M
Fang
Francis G
FG
Vermeulen
Mary W
MW
Gallagher
Brian M
BM
Littlefield
Bruce A
BA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D018942:Macrolides; D008386:Marine Biology; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D043823:Taxoids / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D018942:Macrolides; D043823:Taxoids; C117305:laulimalide