title: In vitro and in vivo anticancer activities of synthetic (-)-laulimalide, a marine natural product microtubule stabilizing agent.
abstract: 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.
authors.affiliation: Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA.
authors.forename: Junke
authors.initials: J
authors.lastname: Liu
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Towle
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Cheng
authors.forename: Philip
authors.initials: P
authors.lastname: Saxton
authors.forename: Cathy
authors.initials: C
authors.lastname: Reardon
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wu
authors.forename: Erin A
authors.initials: EA
authors.lastname: Murphy
authors.forename: Galina
authors.initials: G
authors.lastname: Kuznetsov
authors.forename: Charles W
authors.initials: CW
authors.lastname: Johannes
authors.forename: Martin R
authors.initials: MR
authors.lastname: Tremblay
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Zhao
authors.forename: Marc
authors.initials: M
authors.lastname: Pesant
authors.forename: Francis G
authors.initials: FG
authors.lastname: Fang
authors.forename: Mary W
authors.initials: MW
authors.lastname: Vermeulen
authors.forename: Brian M
authors.initials: BM
authors.lastname: Gallagher
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Littlefield
mesh_terms: 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
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D018942:Macrolides; D043823:Taxoids; C117305:laulimalide