78111-14-5Relevant articles and documents
Selective elimination of human pluripotent stem cells by a marine natural product derivative
Kuo, Ting-Fang,Mao, Di,Hirata, Nao,Khambu, Bilon,Kimura, Yasuhisa,Kawase, Eihachiro,Shimogawa, Hiroki,Ojika, Makoto,Nakatsuji, Norio,Ueda, Kazumitsu,Uesugi, Motonari
supporting information, p. 9798 - 9801 (2014/08/05)
One of the current obstacles to stem cell therapy is the tumorigenic potential of residual undifferentiated stem cells. The present study reports rediscovery of a synthetic derivative of okadaic acid, a marine polyether toxin, as a reagent that selectively induces the death of human pluripotent stem cells. Cell-based screening of 333 cytotoxic compounds identified methyl 27-deoxy-27-oxookadaate (molecule 1) as a substrate of two ATP-binding cassette (ABC) transporters, ABCB1 (MDR1) and ABCG2 (BCRP), whose expression is repressed in human embryonic stem cells and induced pluripotent stem cells. The results demonstrate that selective elimination of human pluripotent stem cells can be achieved by designing cytotoxic small molecules with appropriate ABC-transporter selectivity.
An analysis of the mechanisms involved in the okadaic acid-induced contraction of the estrogen-primed rat uterus
Arteche, Elena,Strippoli, Giuseppe,Loirand, Gervaise,Pacaud, Pierre,Candenas, Luz,Molto, Juan-Carlos,Souto, Luisa,Fernandez, Javier,Norte, Manuel,Martin, Julio D.,Savineau, Jean-Pierre
, p. 201 - 207 (2007/10/03)
The contractile effect of okadaic acid (OA) and its derivatives was investigated in the rat uterus. OA (20 μM) induced a transient contraction which, after plateauing, slowly decreased. The structurally related compound okadanol (20 μM) failed to induce any significant contraction. Conversely, the synthetic compound methyl okadaate (20 μM) and the naturally occurring ester 7'-hydroxy-4'-methyl-2'-methylen-hept-4'(E)-enyl okadaate (20 μM) were as active as the free acid. The OA-induced contraction was unaffected in the presence of neomycin (5 mM), mepacrine (30 μM), 1-[N,O-bis(1,5- isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (10 μM), calphestin C (3 μM) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (30 μM). The calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1- naphthalenesulfonamide bydrochloride (100 μM) did not modify the amplitude of the OA-induced contraction but significantly increased the rate of tension decay. The myosin light chain kinase inhibitor 1-(5-chloronaphthalene-1- sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride [1 μM) significantly reduced the peak amplitude of the contraction. Staurosporine (0.03-0.1 μM) did not modify the contractile component of the OA-induced response but inhibited the subsequent decrease in tension. In freshly dispersed myometrial cells loaded with the fluorescent Ca++ indicator indo 1, OA did not produce any significant increase in [Ca++](i). OA (5- to 90-min contact) also failed to modify the intracellular levels of arachidonic acid, compared with basal values. These data suggest that in the rat uterus 1) the contractile effect of OA (20 μM) is specifically mediated by inhibition of protein phosphatases type 1 and/or 2A and is related to a direct interaction with the contractile machinery; 2) the decreasing phase of the OA-induced mechanical response could be mediated by a staurosporine-sensitive protein kinase different from protein kinase C.