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PubMed2003

Inhibition of protein kinase C by synthetic xanthone derivatives.

The modulatory activity of two xanthones (3,4-dihydroxyxanthone and 1-formyl-4-hydroxy-3-methoxyxanthone) on isoforms alpha, betaI, delta, eta and zeta of protein kinase C (PKC) was evaluated using an in vivo yeast phenotypic assay. Both xanthones caused an effect compatible with PKC inhibition, similar to that elicited by known PKC inhibitors (chelerythrine and NPC 15437). PKC inhibition caused by xanthones was confirmed using an in vitro kinase assay. The yeast phenotypic assay revealed that xanthones present differences on their potency towards the distinct PKC isoforms tested. It is concluded that 3,4-dihydroxyxanthone and 1-formyl-4-hydroxy-3-methoxyxanthone may become useful PKC inhibitors and xanthone derivatives can be explored to develop new isoform-selective PKC inhibitors.

Alkaloids↗
PubMed2003

Substituted benzo[i]phenanthridines as mammalian topoisomerase-targeting agents.

Several benzo[c]phenanthridine and protoberberine alkaloids, such as nitidine and berberrubine, are known to induce DNA cleavage in the presence of either topoisomerase I or II. Structure-activity studies performed on various analogues related to benzo[c]phenanthridine and protoberberine alkaloids have provided insights into structural features that influence this topoisomerase-targeting activity. Modifications within the A-ring of benzo[c]phenanthridine and protoberberine alkaloids can significantly alter their ability to enhance the cleavable complex formation that occurs between DNA and topoisomerases. Select benzo[i]phenanthridines were synthesized as potential bioisosteres of nitidine and its analogues. In the present study, 2,3-methylenedioxy-8,9-dimethoxybenzo[i]phenanthridine, 2,3-methylenedioxy-8,9-dimethoxy-5-methylbenzo[i]phenanthridine, 2,3,8,9-tetramethoxybenzo[i]phenanthridine and 5-methyl-2,3,8,9-tetramethoxybenzo[i]phenanthridine were synthesized. These benzo[i]phenanthridine derivatives were evaluated for their ability to enhance cleavable complex formation in the presence of topoisomerases and DNA as well as for their cytotoxicity against the human lymphoblastoma cell line, RPMI8402. 2,3-Methylenedioxy-8,9-dimethoxybenzo[i]phenanthridine (4a) and its 5-methyl derivative (4b) are active as topoisomerase I-targeting agents. In contrast to nitidine, the presence of the 5-methyl substituent in the case of 4b is not associated with enhanced activity. Consistent with previous structure-activity studies on nitidine and protoberberine alkaloids, 2,3,8,9-teramethoxybenzo[i]phenanthridine, 5a, and its 5-methyl derivative, 5b, are inactive as topoisomerase I-targeting agents. These studies were extended to an evaluation of the relative pharmacological activities of 2,8,9-trimethoxybenzo[i]phenanthridine, 3,8,9-trimethoxybenzo[i]phenanthridine, and 2,3-methylenedioxy-8,9-methylenedioxybenzo[i]phenanthridine.

Animals↗
PubMed2001

Synthesis of a [18F]labeled chelidonine derivative as a possible antitumor agent.

[(+/-)-[5bRS-(5b alpha, 6beta, 12b alpha)]-5b,6,7,12b,13,14-hexahydro-13-methyl[1,3]benzodioxolo[5,6-c]-1,3-dioxolo[4,5-1] phenanthridin-6-yl]-4-[18F]fluorobenzoate (6b) an aromatic ester of chelidonine was prepared as a possible PET radiotracer. Compound (6b) was prepared in no-carrier-added (n.c.a) form from the 4-N,N,N-trimethylanilinium triflate derivative (5) in one step. The best results were obtained using Kryptofix(2.2.2)/[18F] and DMSO as the solvent at 90 degrees C. Column chromatography afforded the desired compound in overall radiochemical yield of 65-70% (EOS) with a specific activity of about 3000 Ci/mmole and radiochemical purity greater than 95% in 15 min.

Alkaloids↗
PubMed2003

Sensitivity of lysosomal enzymes to the plant alkaloid sanguinarine: comparison with other SH-specific agents.

The influence of the benzo[c]phenanthridine alkaloid sanguinarine on some lysosomal enzyme activities was investigated. Sanguinarine inhibits lysosomal hydrolases in homogenates of cultured mouse fibroblasts. After incubation of mouse fibroblasts in culture with 100 microM sanguinarine an approximately 50% decrease in the activities of N-acetyl-beta,D-glucosaminidase (NAGA), beta-galactosidase (GAL), arylsulfatase and acid lipase was observed. Because the biological activity of sanguinarine might arise from the interaction of its iminium cation with enzyme thiol groups, we compared its effect on NAGA, GAL and acid phosphatase (AcP) activities with the effects of SH-specific reagents p-chloromercuribenzoic acid (CPMA) and N-ethylmaleimide (NEM). Treatment of lysosomal fractions with millimolar concentrations of sanguinarine induces a dose-dependent inhibition of the enzymes; for example, 0.6 mM sanguinarine causes approximately a 40% decrease in AcP and NAGA activities. NEM has similar effects, and increasing the preincubation temperature from 0 degrees C to 37 degrees C intensifies the inhibition due to both agents. CPMA also inhibits the activity of GAL (IC50 0.7 microM), AcP (IC50 12.5 microM) and NAGA (IC50 6.8 microM) in a dose-dependent manner but is more potent than sanguinarine or NEM. Comparative analysis of the primary structures of these enzymes using the program BLAST reveals the presence of highly conserved cysteine residues, which confirms the importance of thiol-groups for their activities. Thus, both the experimental observations obtained in this study and the literature data imply a significant role of redox-based mechanisms in regulating lysosomal functional activity.

Acetylglucosaminidase↗
PubMed2002

Regulation of NFkappaB in hepatic ischemic preconditioning.

BACKGROUND: The second messengers tyrosine kinase (TK) and protein kinase C (PKC) have been implicated in mediating the cellular signaling cascade during hepatic ischemic preconditioning (IPC). We evaluated the role of TK and PKC on the modulation of the transcription factor nuclear factor kappa B (NFkappaB) and its inhibitor IkappaB alpha during IPC. STUDY DESIGN: Yorkshire pigs underwent routine harvest. IPC livers underwent 15 minutes of ischemia and 15 minutes of in situ perfusion before harvest, with or without pretreatment with a TK inhibitor (genistein) or a PKC inhibitor (chelerythrine). During cold storage and reperfusion, tissue extracts were analyzed for IkappaB alpha phosphorylation and NFkappaB levels and for TK and PKC activity by Western blot. RESULTS: Control pig livers demonstrated no change in the levels of TK, PKC, IkappaB alpha, or NFkappaB before cold ischemia. IPC grafts demonstrated activation of TK and PKC with increased IkappaB alpha phosphorylation and NFkappaB levels before cold ischemia. IPC grafts pretreated with genistein demonstrated inhibition of TK activation but not of PKC activation. Genistein-pretreated grafts also demonstrated inhibition of IkappaB alpha phosphorylation and a lack of NFkappaB translocation to the nucleus throughout the entire experiment. IPC grafts pretreated with chelerythrine demonstrated inhibition of PKC activation but not TK activation. Chelerythrine-pretreated grafts also demonstrated IkappaB alpha phosphorylation before cold ischemia and enhanced nuclear levels of NFkappaB. CONCLUSIONS: Data suggest that the role of TK in IPC might be mediated in part by NFkappaB, but PKC does not depend on NFkappaB for its effect. Two parallel signaling pathways might explain these data.

Alkaloids↗
PubMed1999

In vitro activities of antimicrobial agents against Candida species.

OBJECTIVE: Antimicrobial mouthrinses may represent a valid alternative to topical antifungal agents. However, the action of antimicrobials could be affected by the different ingredients incorporated into mouthrinse products. The purpose of the present study was to investigate the in vitro antifungal and fungicidal activities of antimicrobials alone. STUDY DESIGN: A broth macrodilution method was used to determine the minimum inhibitory concentration of 4 antimicrobial agents against Candida species. Minimum fungicidal concentration was also determined. RESULTS: All antimicrobials showed antifungal activity against all tested organisms, but cetylpyridinium chloride received significantly lower minimum inhibitory concentrations (P < .005). Cetylpyridinium chloride also showed a greater fungicidal activity than chlorhexidine digluconate and hexetidine (P< .005), whereas sanguinarine chloride appeared to be less fungicidal against most of the isolates tested. CONCLUSIONS: These findings suggest that cetylpyridinium chloride may be used as a topical antifungal agent. Clinical trials are now required to assess its value in the management of oral candidosis.

Alkaloids↗
PubMed1999

Leukoplakia of the maxillary vestibule--an association with Viadent?

OBJECTIVE: This report investigates a possible correlation between chronic use of Viadent products and the subsequent development of leukoplakia in the maxillary vestibule. STUDY DESIGN: A retrospective review of 88 patients with leukoplakia of the maxillary vestibule is presented. Prevalence of Viadent use was determined in this group and in a group of 100 randomly selected adults who presented themselves for routine preadmission screening at a dental school. RESULTS: Of the patients diagnosed with leukoplakia of the maxillary vestibule, 84.1% reported having used Viadent, whereas the prevalence of use was only 3% in the 100 randomly selected adults. CONCLUSIONS: Use of Viadent products appears to be associated with an increased prevalence of leukoplakia in the maxillary vestibule.

Adult↗
PubMed2000

Role of alpha1A-adrenoceptor in the regulation of glucose uptake into white adipocyte of rats in vitro.

In an attempt to know the functional role of alpha1A-adrenoceptors in adipose tissue, white adipocytes (WAT) of Wistar rats were used to investigate the change of glucose uptake after pharmacological activation of alpha1-adrenoceptors. Methoxamine enhanced the uptake of radioactive glucose into isolated WAT in a concentration-dependent manner. Translocation of glucose transporter (GLUT4) from cytosol to membrane was also stimulated with methoxamine. Action of methoxamine to raise glucose uptake was abolished in WAT pre-incubated with the antagonists, both tamsulosin and WB 4101, at concentrations sufficient to block alpha1A-adrenoceptors. However, chlorethylclonidine (CEC). the antagonist of alpha1B-adrenoceptors, showed the inhibition of methoxamine-induced action only at a higher concentration. Even under the treatment with maximal concentration of CEC, methoxamine can produce action about 80% of the vehicle-treated control. The major role of alpha1A-adrenoceptors in the stimulation of glucose uptake by methoxamine can thus be considered. In the presence of specific inhibitor of phospholipase C (PLC), U73312, methoxamine-stimulated glucose uptake into WAT was reduced in a concentration-dependent manner and U73343, the negative control of U73312, did not affect the action of methoxamine. Moreover, chelerythrine and GF 109203X diminished the methoxamine-stimulated glucose uptake at a concentration sufficient to inhibit protein kinase C (PKC). Inhibition of phosphoinositide-3 kinase (PI-3 kinase) by LY294002 also abolished methoxamine-stimulated glucose uptake. Therefore. the obtained data suggest that an activation of alpha1A-adrenoceptors, presence in WAT, by agonist and/or neurotransmitter may increase the glucose uptake via PLC-PKC pathway and the activation of PI-3 kinase.

Adipocytes↗
PubMed2001

Stimulatory effect of phenylephrine on the secretion of beta-endorphin from rat adrenal medulla in vitro.

In an attempt to investigate the role of alpha1-adrenoceptors in the regulation of opioid secretion from adrenal gland, phenylephrine was employed to investigate the effect on secretion of beta-endorphin-like immunoreactivity (BER) from adrenal medulla of rat in vitro. Phenylephrine enhanced the BER from isolated adrenal medulla in a concentration-dependent manner and this action was abolished by the antagonists of alpha1-adrenoceptors, prazosin and tamsulosin. Investigations of signal pathway further support that an activation of alpha1-adrenoceptors is responsible for the stimulatory effect of phenylephrine on BER secretion from adrenal medulla. In the presence of U73312, the specific inhibitor of phospholipase C (PLC), phenylephrine-induced change of BER was reduced in a concentration-dependent manner but it was not affected by U73343, the negative control of U73312. Moreover, chelerythrine and GF 109203X diminished the action of phenylephrine at concentration sufficient to inhibit protein kinase C (PKC). In conclusion, our results suggest that an activation of alpha1-adrenoceptors in adrenal medulla by phenylephrine may enhance the secretion of opioids from adrenal gland of rat via signals of PLC-PKC pathway.

Adrenal Medulla↗
PubMed2003

Studies on the metabolism and toxicological detection of the Eschscholtzia californica alkaloids californine and protopine in urine using gas chromatography-mass spectrometry.

Eschscholtzia californica preparations are in use as phytopharmaceuticals and as herbal drugs. Studies are described on the metabolism and the toxicological analysis of the Eschscholtzia californica alkaloids californine and protopine in rat urine using gas chromatography-mass spectrometry. The identified metabolites indicated that californine is extensively metabolized by N-demethylation and/or single or double demethylenation with consecutive catechol-O-methylation of one of the hydroxy groups. Protopine, however, only undergoes extensive demethylenation of the 2,3-methylenedioxy group followed by catechol-O-methylation. All phenolic hydroxy metabolites were found to be partly conjugated. The authors' systematic toxicological analysis procedure using full-scan gas chromatography-mass spectrometry after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation allowed the detection of the main metabolites of californine and protopine in rat urine after a dose which should correspond to that of drug users. Therefore, use of Eschscholtzia californica preparations should also be detectable in human urine by the authors' systematic toxicological analysis procedure.

Animals↗
PubMed2003

Electrophoretic investigation of interactions of sanguinarine and chelerythrine with molecules containing mercapto group.

Using mercaptoethanol and (L)-cysteine as representatives of mercapto compounds and capillary zone electrophoresis as experimental technique, it was evidenced that sanguinarine and chelerythrine do not react with the mercapto group of organic compounds at pH 7.4. Their interaction is fast and reversible complexation based on non-bonding intermolecular interaction in which enter uncharged forms of sanguinarine or chelerythrine. A negatively charged group, either bound to the mercapto ligand or supplied from solution, participates in the complexation. Simple 1:1 interaction scheme reported in literature holds therefore only for mercapto compounds bearing anionic group. Stoichiometric binding constants corrected for the abundance of the uncharged alkaloid form at pH 7.4 are of the order of magnitude of 10(4) l/mol and depend on both cations and anions of the background electrolyte. Interaction of sanguinarine and chelerythrine with human or bovine serum albumins does not qualitatively differ from their interaction with simple mercapto compounds. Stoichiometric binding constants for the binding of sanguinarine with human and bovine serum albumins in sodium phosphate buffer pH 7.4, corrected for the abundance of the interacting uncharged form, are 332,000+/-38,400 and 141,000+/-14,400 l/mol, respectively. The former agrees well with the value K=385,000 (or log K=5.59) from static photometric experiments. Constants for the complexation of uncharged chelerythrine with human and bovine serum albumins are 2,970,000+/-360,000 and 1,380,000+/-22,600 l/mol, respectively.

Alkaloids↗
PubMed1997

Rapid and long-term effects of PTH(1-34) on growth plate chondrocytes are mediated through two different pathways in a cell-maturation-dependent manner.

The aims of this study were to clarify the role of cell maturation stage on chondrocyte response to parathyroid hormone (PTH) by examining the effect of PTH(1-34) on alkaline-phosphatase-specific activity (ALPase) of chondrocyte cultures at two distinct stages of maturation, and to determine the signaling pathways used by the cells to mediate this effect. Confluent, fourth passage rat costochondral resting zone (RC) and growth zone (GC) chondrocytes were used. ALPase was measured in the cell layer, as well as in matrix vesicles (MV) and plasma membranes (PM), after the addition of 10(-7) 10(-11) mol/L bovine PTH(1-34), the active peptide, or bovine PTH(3-34), the inactive peptide, to the cultures. PTH(1-34) increased ALPase in the GC cultures at two separate times: between 5 and 180 min, with maximal stimulation at 10 min, and 36 to 48 h. In contrast, PTH(3-34) had no effect. At 10 min and 48 h, PTH(1-34) produced a dose-dependent increase in ALPase of both MV and PM isolated from GC cultures. Addition of forskolin and IBMX to increase cAMP increased ALPase in GC cultures to a level similar to that seen after addition of PTH(1-34). In contrast, the addition of PTH(1-34) to RC cells only increased ALPase between 5 and 60 min, with peak activity at 10 min. As with GC, PTH increased ALPase in both MV and PM. Moreover, the addition of PTH(3-34) or forskolin and IBMX had no effect on ALPase in RC. PTH(1-34) had no effect on GC protein kinase C (PKC) activity; however, the addition of PTH(1-34) to RC caused a dose-dependent increase in PKC activity. H8, an inhibitor of PKA, had no effect on PTH-stimulated ALPase in RC cells, but inhibited the PTH-dependent response in GC cells. In contrast, chelerythrine, an inhibitor of PKC activity, inhibited PTH-stimulated ALPase in RC cells, but had no effect on PTH-stimulated ALPase in GC cells. This study shows that the effect of PTH(1-34) on RC and GC cells is maturation dependent in terms of time course and mechanism. Whereas both cell types exhibit a rapid response to PTH, only GC cells show a long-term response. In GC, the effects of PTH are associated with changes in cAMP and may also involve at least one other pathway, whereas, in RC, the PTH effects appear to be associated with changes in PKC.

1-Methyl-3-isobutylxanthine↗
PubMed1999

Prostaglandins mediate the effects of 1,25-(OH)2D3 and 24,25-(OH)2D3 on growth plate chondrocytes in a metabolite-specific and cell maturation-dependent manner.

Prior studies have shown that 1,25-(OH)2D3 stimulates alkaline phosphatase, phospholipase A2 (PLA2), and protein kinase C (PKC)-specific activities, and production of prostaglandin E2 (PGE2) in growth zone chondrocytes. In contrast, 24,25-(OH)2D3 stimulates alkaline phosphatase and PKC-specific activities but inhibits PLA2-specific activity and PGE2 production in resting zone cells. This indicates that different mechanisms are involved in the action of 1,25-(OH)2D3 and 24,25-(OH)2D3 on their respective target cells. In this study, we examined the hypothesis that differential regulation of prostaglandin production modulates the activity of PKC and alkaline phosphatase. To do this, we examined the effect of the cyclooxygenase inhibitor indomethacin (Indo) on alkaline phosphatase, PLA2, and PKC-specific activities in growth plate chondrocytes treated with these two vitamin D metabolites. In addition, we examined whether inhibition of PKC altered PGE2 production. In growth zone cells, Indo inhibited basal alkaline phosphatase and blocked the 1,25-(OH)2D3-dependent increase in alkaline phosphatase. This effect was due to inhibition of both plasma membrane and matrix vesicle alkaline phosphatase. In resting zone cells, Indo increased basal alkaline phosphatase activity in a dose-dependent manner, but it did not further enhance the 24,25-(OH)2D3-dependent stimulation of this enzyme. The effect of Indo was found in both plasma membranes and matrix vesicles. These data indicate that 1,25-(OH)2D3-dependent increases in alkaline phosphatase-specific activity in growth zone cells are mediated through increased prostaglandin production, whereas 24,25-(OH)2D3-mediated changes in enzyme activity in resting zone cells are mediated through decreased prostaglandin production. Regulation of PLA2 by either 1,25-(OH)2D3 or 24,25-(OH)2D3 in their target cells was unaffected by Indo, indicating that the effect of the vitamin D metabolites on this enzyme is not dependent on changes in PGE2 production. The rapid increase in 1,25-(OH)2D3-dependent PKC-specific activity in growth zone cells was inhibited by Indo, whereas there was a potentiation of the effect of 24,25-(OH)2D3 on PKC activity in resting zone cells. In addition, inhibition of PKC blocked the 1,25-(OH)2D3-dependent increase in PGE2 production in growth zone cells and the 24,25-(OH)2D3-dependent decrease in PGE2 production by resting zone cells. These data indicate that prostaglandins are involved in mediating the rapid effects of 1,25-(OH)2D3 on growth zone cells, and contribute to the effects of 24,25-(OH)2D3 on resting zone cells; in both instances, the vitamin D metabolites exert their effects on PKC through changes in arachidonic acid via the action of PLA2. In addition, PKC by itself may mediate the production of PGE2.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

The inhibitory action of tamoxifen on the contraction of Ascaris suum somatic muscle in response to acetylcholine.

The somatic muscle of Ascaris suum is principally under the excitatory control of neuromuscular junction transmitter, acetylcholine (ACh). However, it has recently been shown that neuropeptides also play an important role in the motor-nervous system and one of these, AF3 (AVPGVLRFamide), also contracts muscle. The events which trigger contraction to ACh and AF3 would appear to be different, with ACh activating a nicotinic acetylcholine receptor whilst the response to AF3 is most likely to involve a G-protein coupled receptor negatively coupled to adenylate cyclase. In order to further elucidate differences in the cellular signalling pathways through which ACh and AF3 elicit muscle contraction, we investigated the actions of protein kinase C inhibitors, tamoxifen and chelerythrine, on the dorsal somatic muscle strip of A. suum. Contractions in response to 1 microM AF3 were potentiated by 17% in the presence of 10 microM tamoxifen (P < 0.05; n = 8); however, contractions in response to 10 microM ACh were markedly inhibited (tamoxifen IC50 44 +/- 18 microM; n = 6). Tamoxifen also blocked muscle cell depolarizations to 5 microM ACh (IC50 4 +/- 1 microM; n = 6) and 1 microM levamisole (IC50 14 +/- 6 microM; n = 4). This was unlikely to be a non-specific effect on the membrane as hyperpolarizations to 10 microM GABA were unaffected (93% of control with 10 microM tamoxifen; n = 6; P > 0.05). However, another inhibitor of mammalian protein kinase C, chelerythrine, did not affect the response either to ACh or AF3 (n = 6).

Acetylcholine↗
PubMed2005

Global kinase screening. Applications of frontal affinity chromatography coupled to mass spectrometry in drug discovery.

Utilizing frontal affinity chromatography with mass spectrometry detection (FAC-MS), we have identified novel applications in the discovery of small-molecule hits to protein targets that are difficult if not impossible to accomplish using traditional assays. We demonstrate for the first time an ability to distinguish between competitive ligands for the ATP and substrate sites of protein kinase C independently in the same experiment and show that ATP competitive ligands using a functionally inactive receptor tyrosine kinase can be identified. This ability of FAC-MS to simultaneously monitor binding at the ATP and substrate binding sites, as well as measure ligand binding to both active and inactive kinases, suggests that FAC-MS can be used as a "global kinase binding assay".

Alkaloids↗
PubMed2002

Protein kinase C activation induces phosphatidylserine exposure on red blood cells.

We have shown previously that red blood cells (RBCs) can be induced to influx Ca(2+) when treated with lipid mediators, such as lysophosphatidic acid and prostaglandin E(2), that are released during clot formation. Since calcium loading of RBCs can lead to both protein kinase C (PKC) activation and phosphatidylserine (PS) exposure, we decided to investigate the possible linkage between PKC activation and membrane PS scrambling using phorbol 12-myristate-13-acetate (PMA), a commonly used activator of PKC. Treatment of RBCs with PMA in a calcium-containing buffer caused immediate PS exposure in an RBC subpopulation. The size of the subpopulation did not change upon further incubation, indicating that not all RBCs are equally susceptible to this treatment. Using a fluorescent indicator, we found a subpopulation of RBCs with elevated intracellular calcium levels. In the absence of extracellular calcium, no PS exposure was found. However, we did find cells with high levels of calcium that did not expose PS, and a variable percentage of PS-exposing cells that did not show elevated calcium concentrations. Inhibition of PKC with either calphostin C, a blocker of the PMA binding site, or chelerythrine chloride, an inhibitor of the active site, diminished the level of formation of PS-exposing cells. However, the inhibitors had different effects on calcium internalization, indicating that a high calcium concentration alone was not responsible for inducing PS exposure in the absence of PKC activity. Moreover, PKC inhibition could prevent PS exposure induced by calcium and ionophore treatment of RBCs. We conclude that PKC is implicated in the mechanism of membrane phospholipid scrambling.

Alkaloids↗
PubMed1996

Mechanism of apoptosis suppression by phorbol ester in IL-6-starved murine plasmacytomas: role of PKC modulation and cell cycle.

We show here that the mode of cell death in IL-6-starved T1165 and T1198 plasmacytoma cell lines is apoptosis, and that it can be suppressed by phorbol ester (PMA) treatment in a protein kinase C (PKC)-mediated process that involves alpha and/or delta isozymes. PMA-induced PKC activation, but not the depletion that follows it, participates in the suppression of apoptosis. Extended PKC activation is necessary but not sufficient for the apoptosis suppression. In addition, the cells must be in a "competent" state, which appears not to be determined by PKC. We observed two points of "competence" during the time between withdrawal of IL-6 and the start of massive cell death: one, immediately after withdrawal, and another, just before onset of apoptosis, at the time corresponding to maximal accumulation of cells in a G0/G1 block imposed by IL-6 withdrawal. Treatment with PMA and other PKC activators resulted in a shift of the cell population to S phase, lifting the G0/G1 block. We propose a model in which cells are rescued in a certain stage of the G1 phase of cell cycle. Death suppression occurs when a transient PMA-induced PKC activation occurs when a significant number of cells are in this part of G1, allowing them to pass the restriction point safely without initiating the cell death program.

Alkaloids↗