New okadaic acid analogues from the marine sponge Merriamum oxeato and their effect on mitosis.
Inhibitors of the G2 DNA damage checkpoint can selectively sensitize cancer cells with impaired p53 tumor suppressor activity to killing by DNA-damaging drugs or ionizing radiation and have been proposed as a promising therapeutic strategy. An extract from the Northeastern Pacific marine sponge Merriamum oxeato showed G2 checkpoint inhibitory activity, and fractionation identified the known dinoflagellate toxin dinophysistoxin 1 (1) and the two novel analogues 27-O-acetylokadaic acid (2) and 27-O-acetyldinophysistoxin 1 (3) as the active compounds. The mixture of 1, 2, and 3 was extremely potent at inhibiting the G2 checkpoint (IC(50) = 1 ng/mL) and cellular protein Ser/Thr phosphatases (IC(50) = 1 ng/mL), and it radiosensitized MCF-7 breast cancer cells expressing mutated p53 at all concentrations tested. However, the mixture of 1, 2, and 3 was also very toxic to cells not exposed to DNA damage (IC(50) = 1 ng/mL), making these compounds poor candidates for therapeutic agents to augment the effectiveness of DNA-damaging therapies.
Britton
Robert
R
Department of Chemistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z1, Canada.
Roberge
Michel
M
Brown
Colleen
C
van Soest
Rob
R
Andersen
Raymond J
RJ
D000818:Animals; D001943:Breast Neoplasms; D001955:British Columbia; D004249:DNA Damage / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D019319:Okadaic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011161:Porifera / Q000737:chemistry*; D011714:Pyrans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C478724:27-O-acetyldinophysistoxin 1; C478723:27-O-acetylokadaic acid; D004791:Enzyme Inhibitors; D011714:Pyrans; D016159:Tumor Suppressor Protein p53; D019319:Okadaic Acid; C051904:dinophysistoxin 1; D010749:Phosphoprotein Phosphatases