Stimulation of prostaglandin production by (2E,6Z,10E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol (plaunotol), a new anti-ulcer drug, in vitro and in vivo

doi:10.1016/0006-2952(87)90296-6

Biochemical Pharmacology

Volume 36, Issue 3, 1 February 1987, Pages 369-375

https://doi.org/10.1016/0006-2952(87)90296-6 Get rights and content

Abstract

Plaunotol [(2E,6Z,10E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol], a new anti-ulcer drug, was investigated for its effect on prostaglandin (PG) production. In cultured cells of 3T6 fibroblasts, plaunotol and its main metabolite (1-carboxylic plaunotol) at concentrations of 10–100 μM increased PGE₂ and PGI₂ production 2- to 4-fold. These compounds increased the release of radioactive arachidonic aud from [¹⁴C]arachidonic acid prelabeled 3T6 fibroblast cells 2-fold at 30 μM, and this increase was inhibited by addition of mepacrine, a phospholipase inhibitor. Plaunotol and its main metabolite had no effect on PG cyclooxygenase activity. These results indicate that plaunotol and its main metabolite stimulate PG production by activating cellular phospholipase. In gastric-mucosa slices, PGE₂ and PGI₂ production was increased significantly either by oral administration of plaunotol to rats at a dose of 300mg/kg or by addition of the main metabolite to the incubation medium. All these results suggest that plaunotol increases the PG levels in gastric mucosa by stimulating the PG biosynthesis, particularly the cellular phospholipase activity. The increased levels of PG may participate in the anti-ulcer activity of plaunotol.

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Cited by (29)

Investigation of plaunoi-loaded micro/nanoemulsions for the treatment of dermatitis: Formulation, evaluation and skin irritation studies
2011, Journal of Drug Delivery Science and Technology
The main objective of this work was to formulate microemulsions and nanoemulsions as delivery vehicles for plaunoi extract (Croton stellatopilosus Ohba) to treat dermatitis. Plaunotol, a constituent of plaunoi, has been shown to possess antimicrobial activity. In this work, 2 % w/w plaunoi-loaded formulations were prepared and investigated for their physical property (size and viscosity), efficacy and safety. The plaunoiloaded microemulsions (ME1-P (w/o), ME2-P (o/w)) and nanoemulsion (NE-P (o/w)) had different average sizes and apparent viscosities. Using modified Franz diffusion cell and a synthetic membrane, the release rate of plaunotol from NE-P was found to be the highest. With regard to the in vitro skin penetration, only o/w microemulsion (ME2-P) could deliver plaunotol through the newborn pig skin into the receptor fluid. Unlike ME1-P, the accumulation of plaunotol within the excised newborn pig skin was observed in ME2-P and NE-P. The antimicrobial property of the formulations was further investigated using a cylinder- plate method. Staphylococcus aureus, Staphylococcus epidermidis and Propionibacterium acnes were the tested gram microorganisms. It was found that the plaunoi-loaded formulations exhibited somewhat improved antibacterial activity for S. aureus and S. epidermidis when compared with the blank formulations. The skin irritation was not observed in all treated rabbits for the nanoemulsion NE-P. Both ME1-P and ME2-P showed slight erythema. These results suggest a potential use of nanoemulsions for topical delivery of plaunoi extract.
Plaunotol and Geranylgeraniol Induce Caspase-Mediated Apoptosis in Colon Cancer
2009, Journal of Surgical Research
Citation Excerpt :
Plaunotol is a nonpeptide isoprenoid derived from the tree oil extracted from the leaves of plau-noi, widely used as an anti-ulcer drug in Japan. Although several mechanisms of its anti-ulcer properties have been clarified, only few reports on its effects on cancer are found in the medical literature [15–17], including 2 from our laboratory [6, 7]. We have previously demonstrated that plaunotol is a promising anticancer agent, due to a direct inhibitory effect on gastric cancer cells as well as an anti-angiogenic effect.
Plaunotol, a kind of isoprenoid extracted from a Thai medical plant, plau-noi, is structurally similar to geranylgeraniol (GGOH), another isoprenoid reported to exert strong anticancer effects. Recently, we have reported on its inhibitory effects on tumor angiogenesis and direct effects on gastric cancer cells. Here, we aimed to test whether plaunotol could have some therapeutic effect on colon cancer.
Human colon cancer cell line DLD1 was used. Tumor cells were cultured in the presence of plaunotol or GGOH, and their proliferation was measured by MTS assay. Apoptosis was evaluated by Annexin V and propidium iodide double-staining or terminal-deoxynucleotidyl assay. The activation of caspase-3, -8, and -9 was analyzed by flow cytometry and Western blot analysis for PRRP cleavage.
Plaunotol and GGOH strongly inhibited the proliferative activity of DLD1, dependent on induction of apoptosis. The induction of apoptosis by either plaunotol or GGOH was dependent on the activation of both caspase-8 and caspase-9 pathways.
Plaunotol would be a potential anticancer agent against colon cancer, and since it is already available in Japan and Thailand for clinical use as an anti-ulcer/antigastritis agent, clinical trials will be designed to confirm the present findings.
(2E,6Z,10E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1- ol (plaunotol) increases cyclooxygenase-2 expression via nuclear factor κB and cyclic AMP response element in rat gastric epithelial cells
2005, European Journal of Pharmacology
Plaunotol, [(2E,6Z,10E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol], a gastroprotective agent, increases the prostaglandin production in the gastric mucosa and accelerates ulcer healing. The precise mechanisms underlying the gastroprotective actions by plaunotol are not known. On the other hand, cyclooxygenase (COX)-2 is a key enzyme in PGE₂ production and its induction is thought to have an important role in ulcer healing. We investigated the mechanism of plaunotol-mediated COX-2 induction in rat gastric epithelial (RGM1) cells. We used a PGE₂ enzyme-linked immunoassay kit and Western blot analysis to measure PGE₂ production and COX-2 induction with plaunotol treatment in serum-starved RGM1 cells. In addition, gel-shift assay, Western blot analysis and a reporter assay were performed to observe which Cox-2 promoter was involved in plaunotol-induced Cox-2 expression. The findings indicated that plaunotol treatment dose-dependently increased COX-2 expression and PGE₂ production. The nuclear factor κB (NF-κB) and cyclic AMP response element (CRE) sites of the COX-2 gene promoter were critical to plaunotol-mediated COX-2 expression.
In conclusion, plaunotol induced COX-2 expression and increased PGE₂ production in serum-starved RGM1 cells via activation of the NF-κB and CRE sites of Cox-2 gene promoters.
Troglitazone, a new antidiabetic agent possessing radical scavenging ability, improved decreased skin blood flow in diabetic rats
1998, Life Sciences
Troglitazone is a new class of antidiabetic agent possessing radical scavenging ability similar to vitamin E. Because of this abiliry, it is expected to improve decreased nutritive capillary blood flow in diabetes. In the present study, we investigated the effects of troglitazone on skin blood flow(SBF) in normal and streptozotocin(STZ)-induced diabetic rats. Effects of troglitazone on vasodilation, PGI₂ and PGE₂ production were also assessed in perfused hindlimb, isolated rat aorta rings and 3T6 fibroblasts, respectively. SBF at the base of the tail was decreased in STZ diabetic rats(2.1 ± 0.2 ml/min/100 g) compared with normal rats(3.8 ± 0.2 ml/min/100 g). This decrease of SBF was significantly improved(2.9 ± 0.2 ml/min/100 g) by troglitazone treatment(~ 220 mg/kg/day) for 7 days in STZ diabetic rats without alleviating hyperglycemia. Similar troglitazone treatment(~160 mg/kg/day for 7 days) tended to increase SBF(~ 30 %) even in normal rats. In normal rats, subcutaneous administration of troglitazone(60 mg/kg) acutely increased SBF and, this increase was suppressed by 70 % with pretreatment(10 mg/kg s.c.) of indomethacin, cyclooxygenase inhibitor, suggesting that troglitazone inaeases skin blood flow predominantly by increasing PGI₂ and PGE₂ production. In hindlimb perfusion under fixed flow rate, troglitazone infusion(20 μM) significantly decreased perfusion pressure by 13 %, which reflects vasodilation of blood vessels. This decrease of perfusion pressure was inhibited by concomitant infusion of indomethacin but not N-monomethyl-L-arginine, inhibitor of nitric oxide synthase. In vitro studies, using isolated rat aorta rings, revealed that troglitazone(4.5 to 45 μM) increases PGI₂ production by 31 and 70%, respectively. In 3T6 fibroblast(a component of skin tissue), troglitazone at a low dose of 0.3 μM increased PGI₂ and PGE₂ by 200 % and 25 %, respectively. Overall all, these results suggest that troglitazone increases nutritive SBF probably by virtue of its radical scavenging thus the resulting in an increase in PGI₂ and PGE₂ production in blood vessels and fibroblast. Troglitazone may alleviate impaired microcirculation in diabetic: patients through these effects.
Effects of anti-inflammatory drugs and agents that modify intracellular transduction signals or metabolic activities in inflammatory cells on interleukin-1 induced cartilage proteoglycan resorptionin vitro
1992, Pharmacological Research
The actions of (a) anti-inflammatory drugs possessing a wide range of chemical structures and pharmacological actions, and (b) agents which modify intracellular transduction signals or metabolic functions were investigated for their potential to modifyin vitro the proteoglycan (PrGn) resorption in bovine nasal cartilage induced by interleukin-1 alpha (IL-1). It was found that: (a) none of the conventional anti-inflammatory agents exhibited any inhibitory effects on IL-1 induced resorption of PrGns with the exception of the weak effects observed with the iron chelator, desferrioxamine, a cryogenine derivative J13-1-0, and myalex; (b) the antitumour agent cisplatin was a potent inhibitor but the analogue, transplatin, which does not inhibit DNA synthesis was without effect; (c) suramin, an inhibitor of cartilage degrading enzymes from leucocytes, also inhibited 1L-1 induced resorption, as did natural somatomedin C (insulin-like growth factor= IGFα) but not agents previously shown to inhibit the lymphocyte mitogenic responses to IL-I (e.g. α-melanocyte stimulating hormone, phenylglyoxal); (d) while no effects were observed with drugs that alter the intracellular production of cyclic AMP, those which affect uptake of calcium ions did inhibit proteoglycan resorption by IL-1. The results suggest that IL-1 induced cartilage PrGn degradation can be regulated at the level of transcriptional production of intracellular PrGn degrading enzymes or their activity, regulating calcium uptake into chondrocytes or by overcoming the PrGn degradation from IL-1 by stimulating the synthesis of these macromolecules.
Anti-Ulcer Drugs of Plant Origin
1991, Progress in Medicinal Chemistry
This chapter describes both established and experimental anti-ulcer drugs from plants and attempts to relate structural features in active compounds to the pathology of peptic ulceration. Plants provide an alternative strategy in the search for new drugs. The exploitation of the old herbal books led to the discovery of the first modern anti-ulcer drug—carbenoxolone. Despite this early success, plants are still largely unexploited as sources of new drugs. Medicinal plants offer the chemist and the pharmacologist a rich source of new molecules to explore as future drugs or as biochemical tools to unravel aetiology. Many medicinal plants listed in ancient pharmacopoeias have a reputation for treating gastric disorders. Crude drugs derived from such plants contain only low concentrations of active substances and in consequence are often largely ineffective. Before considering the mode of action of carbenoxolone sodium, it is necessary to understand the pathology of peptic ulcer formation. Peptic ulcer is a convenient term that covers both gastric and duodenal ulcers. An examination of the phytochemical literature for anti-ulcer molecules reveals that anti-ulcer activity is not confined to one class of compound. Such activity is usually discovered by screening various plant molecules against one or more animal models. Biochemical information on the role of plant drugs in preventing ulceration is of increasing importance.

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Stimulation of prostaglandin production by (2E,6Z,10E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol (plaunotol), a new anti-ulcer drug, in vitro and in vivo

Abstract

Gastroenterology

Gastroenterology

Prostaglandins

Gastroenterology

Gastroenterology

Biochem. Pharmac.

Biochem. Pharmac.

Prostaglandins

J. biol. Chem.

Biochem. Pharmac.

Chem. pharm. Bull., Tokyo

Pharmacometrics

Pharmacometrics

Prog. Med.

Prog. Med.

Prog. Med.

Am. J. dig. Dis.