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Macrocyclic marine natural products: leads in the drug discovery process for potential glioma therapeutics
Author(s) -
Ishmael Jane Elizabeth,
Serrill Jeffrey Daniel,
Wan Xuemei,
Alani Adam W,
McPhail Kerry L
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1272.10
Subject(s) - natural product , drug discovery , in vivo , cell culture , programmed cell death , cancer , depsipeptide , biology , cancer cell , drug action , drug , glioma , cell growth , cell , chemistry , cancer research , pharmacology , biochemistry , apoptosis , genetics
The chemical diversity found in Nature has been a significant source of inspiration for drug design and development, particularly in the areas of cancer and infectious disease . The utility of natural products as drug leads is attributed to the fact that these molecules have typically evolved to bind very specific biological targets and have the potential to reveal new mechanisms of drug action and cell death signaling. We previously reported the discovery of coibamide A, an unusual N‐methyl‐stabilized depsipeptide that was isolated from a marine cyanobacterium growing within the marine reserve of Coiba National Park in Panama. Testing of coibamide A in the National Cancer Institute in vitro 60 cancer cell line panel revealed an unmatched selectivity profile indicative of a unique mechanism of action. Specifically, coibamide A showed pM to nM potency as a growth inhibitor against many of the cell lines tested, including all six cell lines representing human glioblastoma. Recognizing that coibamide A is an unusual chemical scaffold, with the potential to probe new aspects of cell biology for cancers that remain very difficult‐to‐treat, the goal of the present study was to evaluate the antitumor properties of the natural product in a range of cell‐based assays and in vivo. We have confirmed that coibamide A induces a G 1 arrest and triggers glioblastoma cell death in vitro and, in preliminary testing, found this compound to significantly reduce tumor volume in vivo in a subcutaneous mouse model of glioblastoma. Coibamide A also has antiangiogenic properties and potently decreases expression of secreted VEGFA and mature forms of VEGFR2 in cell‐based assays. Morphological and biochemical evaluation of coibamide A‐induced action, relative to select compounds for which the mechanism of action is already know, suggests that coibamide A is functionally similar to another cyanobactial metabolite, apratoxin A, and may target the cellular secretory pathway to promote decreases in both VEGFA and VEGFR2 expression. A better understanding of the mechanism of action of coibamide A has led to the use of a functional bioluminescence‐based assay, that is currently being used in a pilot project to screen and profile compounds from the Oregon Translational Research and Development Institute (OTRADI) small molecule library, toward the goal of identifying compounds that inhibit the secretory pathway of human glioblastoma multiforme cells. Support or Funding Information This work was supported by an American Brain Tumor Association (ABTA) Discovery Grant (to JEI) and funding from the Oregon State University (OSU) General Research Fund.Coibamide‐producing organism and lariat depsipeptide structure