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PubMed1975

Epidemic dropsy in New Delhi.

Forty-five cases of epidemic dropsy were studied from an epidemic in New Delhi. Argemone oil contamination was found in the mustard oil used for cooking. Sanguinarine was detected in the eight urine samples collected within 2-3 weeks of onset of dropsy and its concentration ranged from 0.4 to 3.6 mug/100 ml. Three of the 18 sera were positive for sanguinarine, the concentration being 1.2, 1.6 and 3.6 mug/100 ml. The clinical manifestations and epidemiological factors were studied. Edema of the legs was the most consistent clinical finding, and was present in all the patients. In contrast to the earlier epidemics, three striking features were pigmentation in 33%, hair loss in 77.7% and nontender hepatomegaly in 24.4% of cases. A follow-up of 10 months showed almost complete recovery in all.

Adolescent↗
PubMed2004

Chronic exercise improves myocardial inotropic reserve capacity through alpha1-adrenergic and protein kinase C-dependent effects in Senescent rats.

We have previously demonstrated that alpha(1)-adrenergic (AR)-mediated contraction is diminished in the senescent rat heart, in part due to alterations in protein kinase C (PKC) signaling. Since chronic exercise training (EX) can exert independent effects on increasing alpha(1)-AR contraction in the adult rat heart, we sought to determine whether age-related defects in alpha(1)-AR contraction could be reversed by chronic EX. We further hypothesized that improved alpha(1)-AR contraction by EX may be PKC dependent. Adult (4 months; Y) and aged (24 months; O) male F344 rats were treadmill-trained (n = 12-13/group; TR) at approximately 70% of VO(2max) for 12 weeks or remained sedentary (YSED, YTR, OSED, OTR). Training status was verified by plantaris citrate synthase activity and left ventricular (LV) contractile responses (dP/dt) to alpha(1)-AR stimulation were assessed in Langendorff-perfused hearts using the alpha(1)-AR agonist phenylephrine (PE; 10(-5) M) with and without the PKC inhibitor chelerythrine (CE; 10(-6) M). alpha(1)-AR stimulation elicited greater increases in LV dP/dt in hearts isolated from OTR (4525.4 +/- 224.1 mmHg/s) versus OSED (3658.9 +/- 291.0 mmHg/s), while CE abolished PE-induced effects (OTR, 4069.2 +/- 341.2) versus (OSED, 3608.9 +/- 321.2) (p < .01). Upon western blotting, phosphospecific antibodies directed at PKCepsilon (pSer(729)) revealed greater levels in LV isolated from YTR versus YSED, and EX ameliorated aged-related reductions in OSED (p < .001). Basal PKCepsilon mRNA levels were also greater in YTR and OTR versus YSED (p < .01). PE-induced increases in phosphor-PKCdelta (pThr(507)) levels observed in OSED were attenuated in OTR (p < .03). Chronic EX was also associated with significant reductions in PKCalpha (pSer(657)) levels following PE in OTR (p < .002). The results indicate that age-related reductions in alpha(1)-AR contraction can be partially reversed by EX in the rat heart. These results further suggest that alterations in PKC levels underlie, at least in part, EX-induced improvements in alpha(1)-AR contraction.

Aging↗
PubMed1996

Protein kinase C activation during progesterone-stimulated acrosomal exocytosis in human spermatozoa.

The involvement of protein kinase C (PKC) in exocytosis of the mammalian sperm acrosome is still a controversial issue. Work carried out thus far has failed to provide direct evidence for the activation of this enzyme upon stimulation with natural agonists of acrosomal exocytosis. We have therefore used progesterone stimulation of the acrosome reaction in human spermatozoa to clarify this issue. In spermatozoa preincubated under conditions known to support capacitation and fertilization in vitro, treatment with progesterone caused a time-dependent stimulation of phosphorylation of at least eight proteins ranging in size from approximately 20-220 kDa. The inclusion of the PKC inhibitors chelerythrine chloride or calphostin C reduced the observed phosphorylation in a concentration-dependent manner. Exogenously supplied phorbol 12-myristate-13-acetate (PMA) or the permeant diacylglycerol 1-oleoyl-2-acetyl-sn-glycerol (OAG), synthetic activators of PKC, also stimulated phosphorylation in preincubated spermatozoa, but inclusion of calphostin C diminished the response. Furthermore, the prior inclusion of the 1,4-dihydropyridine Ca2+ channel antagonist nifedipine also inhibited phosphorylation, suggesting that PKC is activated downstream of Ca2+ channel opening. Exocytosis triggered by progesterone was significantly inhibited by chelerythrine chloride or calphostin C. Both PMA and OAG triggered exocytosis, but the inclusion of chelerythrine chloride significantly inhibited the response; exocytotic responses were seen only in capacitated cells. These results provide the first direct evidence that PKC activation plays a role in the signal transduction pathway underlying acrosomal exocytosis in progesterone-stimulated capacitated spermatozoa.

Acrosome↗
PubMed1996

Effects of protein kinase C activation and inhibition on sperm-, thimerosal-, and ryanodine-induced calcium responses of human oocytes.

Previous data have shown that protein kinase C (PKC) participates in the mechanism of sperm-induced calcium oscillations in mammalian oocytes, but the actual role of this enzyme in the oscillation mechanism is still unknown. In this study we show that drugs modulating PKC activity disturb the oscillations induced by spermatozoa, thimerosal and ryanodine, but in a different way for each of the three oscillogenic agents. Moreover, PKC inhibition interferes with the return of the intracellular free calcium concentration to basal values during the sperm- and ryanodine-induced calcium oscillations, but not during the thimerosal-induced calcium oscillations. When the PKC-modulating drugs were applied before any of the three oscillogens, the subsequent calcium oscillations were also disturbed. However, the first calcium spike induced by spermatozoa and thimerosal was little influenced by PKC activation or inhibition. On the other hand, ryanodine failed to produce any calcium response when the PKC activity was clamped to a high level. These data suggest that sustained high PKC activities impede calcium oscillations by interfering with the opening of the ryanodine-sensitive calcium release channel, whereas sustained low activities of the enzyme paralyse the channel in the open state.

Alkaloids↗
PubMed2002

Different signal transduction pathways are involved during human sperm capacitation induced by biological and pharmacological agents.

Human sperm capacitation involves complex signal transduction mechanisms during which double phosphorylation of the threonine-glutamine-tyrosine motif (P-Thr-Glu-Tyr-P) occurs in some sperm proteins. The objective of this study was to investigate the regulation of this process. Fetal cord serum ultrafiltrate (FCSu), follicular fluid ultrafiltrate (FFu), progesterone and a combination of N(6),2'-O-dibutyryl cAMP (dbcAMP; cell permeant analogue of cAMP) and 3-isobutyl-1-methylxanthine (IBMX; phosphodiesterase inhibitor) were used as inducers of capacitation alone or in combination with inhibitors of protein kinase A (H89), protein kinase C (chelerythrine), protein tyrosine kinase (tyrphostin A47, PP2) and of dual specificity kinase (MEK-like kinases; PD98059). The level of P-Thr-Glu-Tyr-P in sperm proteins of 80 and 105 kDa during capacitation induced by FCSu, FFu and progesterone was regulated by a similar signal transduction pathway and involved receptor type protein tyrosine kinase and dual specificity kinase (MEK or MEK-like) but not protein kinase A or C. However, the level of P-Thr-Glu-Tyr-P in these sperm proteins during capacitation induced by dbcAMP+IBMX was mainly mediated through protein kinase A and C and receptor type protein tyrosine kinase, but not by dual specificity kinase. In conclusion, human sperm capacitation induced by some biological and pharmacological agents is regulated through very different signal transduction pathways.

1-Methyl-3-isobutylxanthine↗
PubMed2006

Site-specific binding of chelerythrine to single cytosine and thymine bulges in DNA hairpins.

Chelerythrine exhibits pronounced antitumor and apoptosis activities. In order to provide insights into the molecular mechanism of its pharmacological effects, binding selectivity of chelerythrine to a series of single-base bulged DNA hairpins has been assayed by using spectrofluorometric technique. The results indicated that chelerythrine binds specifically to C- and T-bulge sites in DNA hairpins, while sanguinarine exhibits extremely weak binding selectivity to any single-base bulged DNA hairpins, although it has very similar structure with chelerythrine.

Alkaloids↗
PubMed1998

TGF-beta- and angiotensin-II-induced mesangial matrix protein secretion is mediated by protein kinase C.

BACKGROUND: Glomerulonephritis is characterized by the accumulation of extracellular matrix protein within the glomerulus. This process, when allowed to proceed unimpeded, leads to glomerulosclerosis and eventually to cessation of glomerular filtration. There is evidence that protein kinase C (PKC) activation plays an important role in mediating at least some of the effects of TGF-beta in vascular smooth-muscle cells. The current study was undertaken to determine whether PKC activity is required for both TGF-beta and angiotensin II (Ang II) to induce mesangial cell matrix protein secretion. METHODS: PKC was inhibited by two separate methods, and [3H]thymidine incorporation was assessed in both the presence and the absence of PKC inhibition. Conditioned medium from cells stimulated with TGF-beta or Ang II was collected and analysed for secreted matrix proteins and sulphated proteins by SDS-polyacrylamide gel electrophoresis and western blotting. RESULTS: Twenty-four-hour incubation of rat mesangial cells with phorbol-12-myristate-13-acetate (PMA) reduced total PKC activity to basal levels. Both TGF-beta and Ang II were mitogenic in mesangial cells, and chronic PMA pre-incubation inhibited this DNA synthesis. TGF-beta-and Ang-II-induced sulphated protein secretion into conditioned medium was markedly attenuated in PKC-downregulated cells. Secretion of the specific matrix proteins laminin and fibronectin by mesangial cells stimulated with either TGF-beta or Ang II was also diminished in PKC-downregulated cells and in cells pre-incubated with the specific PKC inhibitor, chelerythrine. There was no evidence of generalized cell toxicity or decreased non-specific protein synthesis caused by these PKC inhibitors. CONCLUSIONS: PKC is a key intermediary in the process by which TGF-beta and Ang II cause DNA synthesis and mesangial cell matrix protein production. Thus, PKC inhibitors deserve further study as potential therapeutic agents for a variety of glomerular diseases.

Alkaloids↗
PubMed2001

Mechanisms of the apoptotic and necrotic actions of trimethyltin in cerebellar granule cells.

In evaluating mechanisms of trimethyltin (TMT)-initiated neuronal damage, the present study focused on involvement of reactive oxygen species, protein kinase C (PKC), and glutamate receptors. Exposure of cerebellar granule cells to TMT (0.01-0.1 microM) produced primarily apoptosis, but higher concentrations were associated with cellular lactate dehydrogenase efflux and necrosis. TMT increased generation of cellular reactive oxygen species, which was inhibited by either L-NAME (inhibitor of nitric oxide synthase, NOS) or catalase, indicating that both NO and H(2)O(2) are formed on TMT exposure. Since chelerythrine (selective PKC inhibitor) also inhibited oxidative species generation, PKC appears to play a significant role in TMT-induced oxidative stress. The metabotropic glutamate receptor antagonist, MCPG, (but not MK-801) prevented oxidative species generation, indicating significant involvement of metabotropic receptors (but not NMDA receptors) in TMT-induced oxidative stress. NOS involvement in the action of TMT was confirmed through measurement of nitrite, which increased concentration dependently. Nitrite accumulation was blocked by L-NAME, chelerythrine, or MCPG, showing that NO is generated by TMT and that associated changes in NOS are regulated by a PKC-mediated mechanism. Oxidative damage by TMT was demonstrated by detection of elevated malondialdehyde levels. It was concluded that low concentrations of TMT (0.01-0.1 microM) cause apoptotic cell death in which oxidative signaling is an important event. Higher concentrations of TMT initiate necrotic death, which involves both an oxidative and a non-oxidative component. TMT-induced necrosis but not apoptosis in granule cells is mediated by glutamate receptors.

Alkaloids↗
PubMed1998

Altered regulation of L-type channels by protein kinase C and protein tyrosine kinases as a pathophysiologic effect in retinal degeneration.

The effect of protein tyrosine kinases (PTK) on L-type calcium channels in cultured retinal pigmented epithelium (RPE) from rats with retinal dystrophy was investigated. Barium currents through Bay K 8644 (10(-6) M) sensitive L-type channels were measured using the patch-clamp technique. The current density of L-type currents is twice as high and the inactivation time constants are much slower than in cells from nondystrophic control rats. Application of the PTK blockers genistein, lavendustin A, and herbimycin A (all 5 x 10(-6) M) led to an increase of L-type currents. Intracellular application of pp60c-src (30 U/ml) via the patch pipette led to a transient decrease of L-type currents. The protein kinase A (PKA) and PKG blocker H9 (10(-6) M) showed no effect on L-type currents. However, the protein kinase C blocker chelerythrine (10(-5) M) reduced these currents. Up-regulation of PKC by 10(-6) M 4beta-phorbol-12 myristate-13 acetate (PMA) led to a decrease of L-type currents. Additional application of genistein led to a further decrease of these currents. However, intracellular application of pp60(c-src) in PMA-treated cells led to a transient increase of L-type currents. Investigating the calcium response to bFGF application showed that RPE cells from RCS rats used different pathways than control RPE cells to increase cytosolic free calcium. This different pathway does not involve the activation of L-type channels. The present study with RPE cells from rats with retinal dystrophy shows a changed integration of PTK and PKC in channel regulation. Considering the altered response to bFGF in RCS-RPE cells, this disturbed regulation of L-type channels by tyrosine kinases is involved in the etiology of retinal degeneration in RCS rats.

Alkaloids↗
PubMed2000

alpha-Tocopherol and protein kinase C inhibition enhance platelet-derived nitric oxide release.

Platelet activation is tightly regulated by products of the endothelium and platelets including nitric oxide (NO). Excess vascular oxidative stress has been associated with impaired NO release, and antioxidant status has been shown to alter endothelium-derived NO bioactivity. Although physiological levels of a-tocopherol are known to inhibit platelet function, the effect of a-tocopherol on platelet NO release is unknown. Loading platelets with physiologic levels of a-tocopherol increased platelet NO production approximately 1.5-fold (Pa-tocopherol, platelet NO release increased 50% (Pa-Tocopherol-loaded platelets also produced 74% less superoxide as compared with control (Pa-tocopherol inhibited PKC-dependent eNOS phosphorylation as determined by immunoprecipitation. Lastly, platelets isolated from NOS3-deficient mice released 80% less superoxide as compared with control animals (P=0.011), and incubation of NOS III-deficient platelets with 500 mM a-tocopherol only caused a modest additional decrease in platelet superoxide release (NS). Thus, a-tocopherol appears to enhance platelet NO release both in vitro and in vivo through antioxidant- and PKC-dependent mechanisms.

Alkaloids↗
PubMed2005

Pivotal role of NOX-2-containing NADPH oxidase in early ischemic preconditioning.

Reactive oxygen species (ROS)-mediated signaling is implicated in early ischemic preconditioning (PC). A NOX-2-containing NADPH oxidase is a recognized major source of ROS in cardiac myocytes, whose activity is augmented by preconditioning mimetics, such as angiotensin II. We hypothesized that this oxidase is an essential source of ROS in PC. Hearts from wild-type (WT) and NOX-2 knockout (KO) mice were Langendorff perfused and subjected to 35 min ischemia/reperfusion with or without preceding PC or drug treatment. Infarct size was measured by triphenyl tetrazolium chloride staining, and NADPH oxidase activity by lucigenin chemiluminescence. PC significantly attenuated infarct size in WT (26+/-2% vs. control, 38+/-2%, P<0.05) yet was ineffective in KO hearts (33+/-3% vs. control, 34+/-3%). Concomitantly, PC significantly increased NADPH oxidase activity in WT (+41+/-13%; P<0.05), but not in KO (-5+/-18%, P=NS). The ROS scavenger MPG (N-2-mercaptopropionyl glycine, 300 micromol/L) abrogated PC in WT (39+/-2% vs. control, 33+/-1%). CCPA (2-chloro N6 cyclopentyl adenosine, 200 nmol/L), a putative ROS-independent PC trigger, significantly attenuated infarct size in WT, MPG-treated WT and KO hearts (24+/-2, 23+/-1, and 20+/-3%, respectively, P<0.05). Furthermore, CCPA did not augment NADPH oxidase activity over control (+22+/-11%, P=NS). Inhibition of protein kinase C (PKC) with chelerythrine (CHE, 2 micromol/L) completely abrogated both PC (38+/-2% vs. CHE alone, 35+/-2%) and associated increases in oxidase activity (+3+/-10%, P=NS). PKC-dependent activation of a NOX-2-containing NADPH oxidase is pivotally involved in early ischemic PC. However, adenosine receptor activation can trigger a ROS and NOX-2 independent PC pathway.

Acridines↗
PubMed2005

Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling.

Langendorff-perfused rat hearts treated with EPO exhibited significantly improved postischemic recovery of left ventricular developed pressure (LVDP) and reduced infarct size compared with control hearts. Perfusion with the mitogen/extracellular signal-regulated kinase (MEK) inhibitor U0126 just before and concomitant with EPO treatment abolished EPO-induced phosphorylation of the MEK substrate extracellular signal-regulated kinase (ERK) but had no effect of EPO-mediated cardioprotection. EPO treatment of the perfused hearts induced translocation of protein kinase C (PKC) epsilon isoform to the membrane fraction of the hearts and the protective effect of EPO was significantly inhibited by the PKC catalytic inhibitor chelerythrine added before and concomitant with EPO. These data demonstrate that EPO-mediated activation of the PKC signaling pathway before or during ischemia is required for the cardioprotective effect of EPO during ischemia-reperfusion injury. Perfusion with the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 or wortmannin just before and concomitant with EPO treatment attenuated EPO-induced phosphorylation of the PI3K substrate Akt but had no effect on EPO-mediated cardioprotection. However, when wortmannin was added during EPO treatment and continued during reperfusion, EPO-mediated cardioprotection was significantly inhibited. We also show that postischemia EPO treatment at the onset of reperfusion significantly improved recovery of LVDP and reduced infarct size. Postischemia cardioprotection by EPO required the PI3K pathway but was not affected by inhibition of PKC at the time of EPO treatment.

Alkaloids↗
PubMed1997

Volatile anesthetics protect the ischemic rabbit myocardium from infarction.

BACKGROUND: The influence of anesthetic agents on the infarction process in the ischemic myocardium is unclear. This study evaluated the effects of three intravenous and three inhalational anesthetic agents on myocardial infarction within a quantified ischemic risk zone in rabbit hearts subjected to a standardized regional ischemia-reperfusion insult. METHODS: Both in vitro and in situ rabbit models were used to investigate the effects of anesthetic agents on infarct size. In all rabbits the heart was exposed and a coronary artery surrounded with a suture to form a snare for subsequent occlusion. In in situ preparations, both intravenous and inhalational agents were tested, whereas only the latter were used in isolated hearts. Infarct size was determined by triphenyltetrazolium chloride staining. To determine whether an adenosine-mediated protective mechanism was involved, 8-(p-sulfophenyl)theophylline, an adenosine receptor blocker, was added to halothane-treated isolated hearts. Adenosine concentration in the coronary effluent was also measured in isolated hearts exposed to halothane. In other protocols, chelerythrine, a highly selective protein kinase C inhibitor, was administered to both halothane-treated and untreated isolated hearts. RESULTS: Infarcts in the three in situ groups anesthetized with halothane, enflurane, and isoflurane were about one half as large as infarcts in rabbits that underwent anesthesia with pentobarbital, ketamine-xylazine, or propofol. Volatile anesthetics also protected isolated hearts by a similar amount. Both adenosine receptor blockade and chelerythrine abolished cardioprotection from halothane in isolated hearts. Halothane treatment did not increase adenosine release. CONCLUSIONS: The volatile anesthetics tested protected the ischemic rabbit heart from infarction, in contrast to the three intravenous agents tested. Protection was independent of the hypotensive effect of the inhalational agents because halothane also protected isolated hearts, in which changing vascular tone is not an issue and coronary perfusion pressure is constant. Cardioprotection by volatile anesthetics depended on both adenosine receptors and protein kinase C, and thus is similar to the mechanism of protection seen with ischemic preconditioning.

Adenosine↗
PubMed1995

TNF-stimulated arginine transport by human vascular endothelium requires activation of protein kinase C.

OBJECTIVE: The authors determined the endothelial arginine transport mechanism and the potential role of a tumor necrosis factor (TNF)-alpha-mediated signal transduction pathway involving protein kinase C (PKC) in regulating this transport in cultured endothelial cells. SUMMARY BACKGROUND DATA: The vascular endothelium metabolizes arginine to generate nitric oxide (NO), and an increase in NO production can be stimulated by several cytokines. The mechanism(s) responsible for the accelerated arginine transport are poorly understood. METHODS: Arginine transport was assayed in confluent human umbilical vein endothelial cells in the presence of TNF +/- the PKC inhibitor chelerythrine chloride. RESULTS: Carrier-mediated arginine transport was accomplished by two Na(+)-independent transporters, System y+ (80% of total transport) and System b0,+ (20% of transport). Tumor necrosis factor (0.1-2 ng/mL) increased System y(+)-mediated arginine transport in a time- and dose-dependent manner by augmenting System y+ transport maximal capacity (control Vmax = 1325 +/- 60 pmol/mg protein/minute vs. TNF Vmax = 3015 +/- 110 pmol/mg protein/minute, p < 0.01) without affecting transporter affinity (control Km = 30 +/- 1.4 microM vs. 34 +/- 1.3 microM arginine, p = NS). Stimulation was maximal at the 8-hour time point and was inhibited by both actinomycin D and cycloheximide. In addition, inhibition of PKC with chelerythrine abrogated the TNF-augmented arginine transport. Similarly, incubation of cells with the direct PKC activator TPA (phorbol ester 12-myristate 13-acetate) stimulated System y(+)-mediated arginine transport nearly fivefold, secondary to an increase in transporter Vmax (TPA Vmax = 5349 +/- 310 pmol/mg protein/minute, p < 0.001 vs. control), with no change in Km. This TPA-induced stimulation of arginine transport also was blocked by chelerythrine CI, actinomycin D, and cycloheximide. Incubation of TNF-stimulated cells with two NO synthase inhibitors did not reduce transport activity, suggesting that the arginine transporter and the NO synthase enzyme may, in part, be independently regulated.

Alkaloids↗
PubMed2001

The association between Viadent use and oral leukoplakia.

Recently, leukoplakia of the maxillary vestibule was described in patients with no traditional risk factors but who had used Viadent products. We designed a case-control study to evaluate the hypothesis that Viadent users were more likely to have lesions. One hundred and forty-eight cases and controls were identified through the Section of Oral and Maxillofacial Pathology. Cases and controls were administered a questionnaire about Viadent use and other known risks. Results of crude, stratified, and logistic regression analyses showed that use of Viadent products was a risk indicator for leukoplakia (adjusted OR = 9.7, 95% CI = 4.7-21.6), with a strong dose-response relation.

Alcohol Drinking↗
PubMed1998

PKC and tyrosine kinase involvement in amyloid beta (25-35)-induced chemotaxis of microglia.

Microglia are activated by amyloid beta (Abeta) in vivo and in vitro, and Abeta-activated microglia may be involved in the pathogenesis of Alzheimer's disease (AD). We investigated the mechanism of microglial chemotaxis induced by Abeta (25-35), an active fragment of Abeta. Abeta (25-35) 0.1 and 1 nM stimulated microglial chemotaxis. The protein kinase C (PKC) inhibitors chelerythrine (0.5 and 2 microM), calphostin C (1 microM) and staurospine (10 nM) significantly inhibited the microglial chemotaxis induced by Abeta (25-35) (1 nM). The chemotactic effect of Abeta (25-35) on microglia was desensitized by pretreatment of microglia with 1 ng/ml 12-O-tetradecanoylphorbol 13-acetate (TPA). Pretreatment of cells with Abeta (25-35) (1 nM) also desensitized the chemotactic effect by Abeta (25-35) (1 nM). The desensitization by TPA or Abeta (25-35) was inhibited when staurosporine was present in the pretreatment media. The tyrosine kinase inhibitor herbimycin A (0.1 and 1 microM) significantly inhibited the microglial chemotaxis induced by Abeta (25-35) (1 nM). Based on these observations, it seems likely that PKC and tyrosine kinase are involved in the Abeta-induced chemotaxis of microglia.

Alkaloids↗
PubMed2002

Antitumor activity of protein kinase C inhibitors and cisplatin in human head and neck squamous cell carcinoma lines.

Protein kinase C (PKC) plays a pivotal role in signal transduction involved in the control of cell proliferation, differentiation and apoptosis. Interference with such signaling pathways may result in altered tumor cell response to antineoplastic drugs. We investigated the effects of two selective PKC inhibitors as single agents and in combination with cisplatin in cell lines derived from squamous cell carcinomas of the head and neck (SCCHN). Safingol (Saf) is directed against the regulatory domain, whereas chelerythrine (Che) interacts with the catalytic domain of PKC. In six SCCHN cell lines (UM-SCC 11B, 14A, 14C and 22B, 8029NA, and a 5-fold cisplatin-resistant subline 8029DDP). PKC activities ranged between 1 and 158 IU/1 x 10(7) cells, and they were inversely proportional to the amount of cellular epidermal growth factor receptor. Using the colorimetric MTT assay, PKC inhibitors Saf and Che showed comparable dose-dependent growth inhibition. The 50% inhibitory concentrations (IC50) were between 3.8-8.6 microM for Saf and 8.5-13.6 microM for Che with no relationship to PKC activity or cisplatin sensitivity of the respective cell lines. Combinations of cisplatin (IC50 = 0.4-5.8 microg/ml) and either PKC inhibitor (5 microM Saf, 10 microM Che) led to a significant decrease of cisplatin IC50 values in most cell lines. However, comparison with theoretical additive dose-response curves showed additive rather than synergistic effects for both PKC inhibitors.

Alkaloids↗
PubMed2005

In vitro assessment of cytotoxic agent combinations for hormone-refractory prostate cancer treatment.

We have investigated new drug combinations of potential clinical value for treatment of hormone-refractory prostate cancer. Combinations of paclitaxel, carboplatin and mitoxantrone, and combinations of these three drugs with compounds targeting important pathways for cancer progression, 13-cis-retinoic acid and chelerythrine, were assessed. The drugs combinations were incubated for 72 h in steroid-free conditions with two androgen-independent cell lines, DU145 and PC3. Cytotoxicity assay was performed using resazurin and Hoescht 33342. Synergism and antagonism were measured by the combination index, and calculated for each combination by the median-effect method. All six compounds exhibited cytotoxic effects when tested alone. Paclitaxel exhibited the highest and 13-cis-retinoic acid the lowest effect on both cell lines. Paclitaxel demonstrated synergism or additivity with 13-cis-retinoic acid in both cell lines, whereas antagonistic effects were observed when it was tested in combination with carboplatin. Chelerythrine showed additive effects with mitoxantrone in both cell lines and with paclitaxel in PC3 cells. Our results suggest that combination of paclitaxel and 13-cis-retinoic acid, and of chelerythrine with mitoxantrone and paclitaxel, may have clinical value for the treatment of hormone-refractory prostate cancer.

Alkaloids↗