Inhibitors phorbol esters

Mansat, V., Laurent, G. Levade, T., Bettaieb, A., and Jaffrezou, J.P., 1997a, The protein kinase C inhibitors phorbol ester and phosphatidylserine block neutral sphingomyelinase activation, ceramide generation and apoptosis triggered by daunorubicin. Cancer Res. 57 5300-5304. 

Ludwig A, Hundhausen C, Lambert MH, et al. Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM 10 and ADAM 17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules. Comb Chem High Throughput Screen 2005 8 161-171. 

It has been found that the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) inhibitors statins (atorvastatin, pravastatin, and cerivastatin), widely prescribed cholesterol-lowering agents, are able to inhibit phorbol ester-stimulated superoxide formation in endothelial-intact segments of the rat aorta [64] and suppress angiotensin II-mediated free radical production [65]. Delbose et al. [66] found that statins inhibited NADPH oxidase-catalyzed PMA-induced superoxide production by monocytes. It was suggested that statins can prevent or limit the involvement of superoxide in the development of atherosclerosis. It is important that statin... 

In previous studies it has been demonstrated that not only protein kinase C (PKC) activators including phorbol esters (TPA) and diacylglycerol (DAG) inhibited the ability of cell-permeant CER to induce apoptosis (Jarvis et al. 1996), but also that PKC inhibitors enhanced CER-induced apoptosis (Jarvis et al, 1994). From these studies it has been suggested that PKC is a key negative regulator of CER-induced apoptosis. 

Mahadevan LC, Willis AC, Barratt MJ (1991) Rapid histone H3 phosphorylation in response to growth factors, phorbol esters, okadaic acid, protein synthesis inhibitors. Cell 65(5) 775—783... 

Phorbol esters are described as being protein kinase C activators and should be selective inhibitors for caveolae uptake [1 pM Phorbol 12-myristate 13-acetate (PMA) for 30 minutes] (48,68). The inhibition occurs as quickly as five minutes after adding PMA to cell culture medium and is not reversible within five hours (MA104 cells). However, PMA has several other effects on several other pathways. An example of this is that it has been described to stimulate macropinocytosis and transcytosis (see the following). 

Ahn CH, Kong JY, Choi WC, Wang MS (1996) Selective inhibition of the effects of phorbol ester on doxorubicin resistance and P-glycoprotein by the protein kinase C inhibitor l-(5-isoquinolinesulfonyl)-2-methylpipera2inc (H7) in multidrug-resistant MCF-7/Dox human breast carcinoma cells. Biochem Pharmacol 52 393-399... 

Chambers TC, Zheng B, Kuo JF (1992) Regulation by phorbol ester and protein kinase C inhibitors, and by a protein phosphatase inhibitor (okadaic acid) of P-glycoprotein phosphorylation and relationship to drug accumulation in multidrug-resistant human KB cells. Mol Pharmacol 41 1008-1015... 

Ferry DR, Smith A, Malkhandi J, F e DW, deTakats PG, Anderson D, Baker J, Kerr DJ (1996) Phase 1 clinical trial of the flavonoid quercetin pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res 2 659-668 Findik D, Song Q, Hidaka H, Lavin M (1995) Protein kinase A inhibitors enhance radiation-induced apoptosis. J Cell Biochem 57 12-21 Fine RL, Patel J, Chabner BA (1988) Phorbol esters induce multidrug resistance in human breast cancer cells. Proc Natl Acad Sci USA, 85 582-586 Finkenzeller G, Marme D, Hug H (1992) Inducible overexpression of human protein kinase C in NIH 3T3 fibroblasts results in growth abnormalities. Cell Signall 4 163-177... 

Ishii HH, Gobe GC (1993) Epstein-Barr virus infection is associated with increased apoptosis in untreated and phorbol ester-treated human Burkitt s lymphoma (AW-Ramos) cells. Biochem Biophys Res Commun 192 1415-1423 Ishii H, lirousek MR, Koya D, Taka C, Xia P, Clermont A, Bursell S-E, Kern TS, Balias LM, Heath WF, Stramm LE, Feener EP, King GL (1996) Amelioration of vascular dysfunctions in diabetic rats by an oral PKC inhibitor. Science 272 728-731... 

Nixon JS (1997) The biology of protein kinase C inhibitors. In Molecular Biology Intelligence Unit Protein Kinase C, PJ Parker and LV Dekker (eds.), R.G. Landes Company, Austin, TX, Springer-Verlag, Heidelberg, 205-236 Noe V, Ciudad CJ (1995) Protein kinase C inhibitors reduce phorbol ester-induced resistance to methotrexate in Chines hamster ovary cells. Biochem Pharmacol 50 337-346... 

In contrast to cAMP, a stimulation of PKC with phorbol esters (TPA) has been shown to play an important role in the downregulation of gap junctional coupling [Yancey et al., 1982]. Since reestablishment of intercellular coupling was not seen after wash out of TPA in the presence of the protein synthesis inhibitor, puromycin [Fitzgerald et al., 1983], the phorbol ester probably induces the elimination of junctional channels under these conditions. Thus, it might be possible that PKC is involved in the regulation of channel degradation. 

Obviously, there is some kind of cross-talk between PKC and cAMP in the modulation of intercellular coupling, since cAMP can inhibit the uncoupling effect of phorbol esters if cells are exposed to both agents from the start of the experiment [Kanno et al., 1984], but this protective effect can be abolished by the protein synthesis inhibitor cycloheximide [Enomoto et al., 1984] in Balb/ cells. 

Laurence, J., Sikder, S.K., Jhaveri, S., and Salmon, J.E., Phorbol ester-mediated induction of HIV-1 from a chronically infected promonocyte clone blockade by protein kinase inhibitors and relationship to tat-d i rected frans-activation, Biochem. Biophys. Res. Commun., 166, 349,1990. 

Dekker LV, De Graan PN, Pijnappel P et al (1991) Noradrenaline release from streptolysin O-permeated rat cortical synaptosomes effects of calcium, phorbol esters, protein kinase inhibitors, and antibodies to the neuron-specific protein kinase C substrate B-50 (GAP-43). J Neurochem 56 1146-53... 

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