Phorbol dibutyrate

In 1990, researchers at Bristol-Myers Squibb reported the isolation of Bmy-41950 (322) from S. staurosporeus strain R10069 (ATCC 55006). This isolate showed in vitro activity against human colon cancer cells (HCT-116) (307). Two years later, Isono et al. reported the isolation of the same natural product from a different Streptomyces sp., S. platensis subsp. malvinus RK-1409 and named it RK-1409 (7-oxostaurosporine) (322) (308,309). In nature, this isolate was obtained in its optically active form [ Id + 38.3 (c 0.06, CHCI3) (309). The PKC inhibitor RK-1409 (7-oxostaurosporine) inhibited the morphological change of a human erythroleukemia cell line, K-562, induced by phorbol 12,13-dibutyrate (PDBu), and also showed a weak antimicrobial activity against Chlorella vulgaris and Pyricularia oryzae (308). 

Yashpal, K., Pitcher, G. M., Parent, A., Quirion, R., Coderre, T. J. Noxious thermal and chemical stimulation induce increases in 3H-phorbol 12,13-dibutyrate binding in spinal cord dorsal horn as well as persistant pain and hyperalgesia, which is reduced by inhibition of protein kinase C, J. Neurosci. 1995, 15, 3263-3272. 

In addition to activation by stretch, MAPK activity rises in response to pharmacological stimulation in contractile smooth muscle (Adam et al., 1995 Katoch and Moreland, 1995). Porcine carotid arteries stimulated with KCl, phorbol 12,13-dibutyrate (PDBu), or histamine demonstrate elevated levels of active MAPK. The activities of p42 APK g d p44MAPK jj-,. crease in tandem under all conditions tested that is, KCl, PDBu, and histamine do not preferentially activate one MAPK isoform over the other isoform. With KCl and histamine stimulation, MAPK activity reaches a maximum within several minutes. PDBu induces a more slowly developing increase in MAPK activity that is maintained for at least one hour. These data suggest that increases in intracellular free calcium, and/or the stimulation of protein kinase C, in vascular smooth muscle result in MAPK activation. Pharmacological increases in MAPK activity are in addition to the levels that result from the application of mechanical load. 

PKC activity in intact cells can be stimulated by phorbol esters, for example, phorbol 12,13-dibutyrate (PDBu), which are not metabolized by cells and, therefore, can produce a prolonged stimulation of PKC. In addition, cell-permeant DAG analogues such as dioc-tanoglycerol (DiC8) and l-oleoyl-2-acetylglycerol (OAG) can activate PKC. 

The PLC-Dependent Mechanisms. The PLC-dependent mechanisms, in contrast to the PKA-dependent signaling system, are important regulators of basal PG production. PG synthesis is associated with activation of PLC and subsequent production of diacylglycerol, inositol-1,4,5-triphosphate, release of Ca ", and Ca -induced activation of PKC (1). Stimulation of PKC by phorbol 12,13-dibutyrate activates PGF secretion by bovine endometrial cells (3). In hamster ovarian cells and rabbit amnion cells, OT activated production of both PGE and PLC, which suggests that the PLC-dependent signaling pathway not only controls basal PG secretion, but also mediates the effect of OT on this process (9). 

The binding of [20- H]phorbol 12,13-dibutyrate to peritoneal macrophages was similar in both nor-... 

In anaesthetised new-born pigs (1 to 5 days old) of either sex, injury of moderate severity (1.9 to 2.1 atm) induced by the lateral fluid percussion brain injury technique phorbol 12,13-dibutyrate (1 imol/l) increased superoxide dismutase-inhibitable nitroblue tetrazoHum reduction from 1 1 to 37 5 pmol/mm (Armstead 1999). 

Protein kinase C influenced cellular sensitivity to cisplatin. Activators of protein kinase C, such as phorbol 12,13-dibutyrate, enhanced the sensitivity of human small cell lung cancer H69 cells to cisplatin by 2-fold but had no effect on the sensitivity of cisplatin-resistant H69 cells to cisplatin (Busu et al. 1996). The maximum sensitisation was achieved with 10 nM phorbol 12,13-dibutyrate and blocked by down-regulation of protein kinase C with higher concentrations of phorbol 12,13-dibutyrate (1 jiM) or bryostatin 1 (0.1 p,M). H69 cells expressed conventional protein kinase Ca and -P, novel protein kinase C6, atypical protein kinase and -i, and novel/atypical protein kinase Cp,. A decrease in conventional protein kinase Ca and -P and an increase in novel protein kinase C6 were associated with the cisplatin-resistant phenotype. 

The (Zy and ( )-unsaturated lactones 73 and 74 have been prepared as analogues of diac glycerols and found to be more inhibitory of [ H-20]-phorbol-12,13-dibutyrate binding to protm kinase C than the corresponding saturated derivatives. ... 

Pasti, G., E. Rivedal, S.H. Yuspa, C.L. Herald, G.R. Pettit, and P.M. Blumberg Contrasting Duration of Inhibition of Cell-Cell Communication in Primary Mouse Epidermal Cells by Phorbol 12,13-Dibutyrate and by Bryostatin 1. Cancer Res. 48,447 (1988). 

CoMFA = comparative molecular field analysis PDBU = phorbol-12,13-dibutyrate PKC = protein kinase C. 

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