Gastroprotective effect of anti-cancer compound rohitukine: possible role of gastrin antagonism and H+ K+-ATPase inhibition

Abstract

The present study was designed to evaluate the anti-ulcerogenic properties of an alkaloid chromane, rohitukine from Dysoxylum binectariferum. Anti-ulcer potential of rohitukine was assessed in cold restrained, pyloric ligated and ethanol induced ulcers in rats. In addition, rohitukine was tested in vitro for H(+) K(+)-ATPase inhibitory activity in gastric microsomes. Moreover, we studied the role of rohitukine on the cytosolic concentration of Ca(2+) in parietal cell-enriched cell suspension in order to ascertain its mechanism of action. Cytoprotective activity was evaluated through PGE(2) level. Rohitukine significantly attenuated the ulcers in cold restraint ulcer (CRU) model in a dose-related manner. Moreover, it significantly lowered the free acidity and pepsin activity in pyloric ligated rats while improved the depleted level of mucin. Furthermore, rohitukine significantly reversed the cold restrained-induced increase in gastrin level. Our in vitro study revealed that rohitukine moderately inhibited the microsomal H(+) K(+)-ATPase activity with respect to positive control omeprazole. Furthermore, rohitukine potently antagonized the gastrin-elicited increase in cytosolic Ca(2+) level in parietal cell-enriched suspension. In ethanol-induced gastric lesions in rats, rohitukine significantly inhibited the formation of erosions and increased PGE(2) content showing more potency than reference drug sucralfate. Our results thus suggest that rohitukine possess significant anti-ulcer and anti-gastrinic activity in rats. It is likely that gastro-protective influences of rohitukine are dependent partly on its acid-lowering potential and partly on cytoprotective property. The acid-reducing effect of rohitukine might be attributed to its lowering effect on gastrin production and/or antagonism of gastrin-evoked functional responses of parietal cells. Thus, rohitukine represent a useful agent in the treatment of peptic ulcer disease.

Rohitukine inhibits in vitro adipogenesis arresting mitotic clonal expansion and improves dyslipidemia in vivo

“…Rohitukine was isolated and characterized as mentioned previously ( 16 ). Briefl y, air-dried, powdered stem bark of Dysoxylum binectariferum (2.0 kg) was extracted with distilled ethanol (5 × 5.0 liters) by cold percolation.…”

“…f. (Maliaceae) and Amoora rohituka . It had earlier been reported for various biological activities, namely anti-infl ammatory, anticancer, immunomodulatory, and antiulcer properties (15)(16)(17)(18)(19)(20). Two of its analogs, Flavopiridol and P-276-00, are currently being evaluated in advanced phase 2 clinical trials for potential anticancer therapy ( 15 ).…”

Pharmacokinetics, Tissue Distribution and Plasma Protein Binding Studies of Rohitukine: A Potent Anti-hyperlipidemic Agent

“…The most active fraction F2 was repeatedly chromatographed over a silica gel (100-200 mesh) column and successively eluted with hexane, chloroform, and chloroform-methanol mixtures (19:1, 9:1, 4:1 and 7:3, v:v), while chloroform and chloroform-methanol mixture 19:1 yielded a brown powdered compound as major constituent (1.2 g). It was crystallized in methanol and characterised as rohitukine [11,12]…”

“…1a), the foremost chromone alkaloid isolated from the stem bark of D.binectariferum (Family-Meliaceae), has been identified as 5,7-dihydroxy-8-((3S,4R)-3-hydroxy-1-methylpiperidin-4-yl)-2-methyl-4H-chromen-4-one [4][5][6][7]. RH has assorted pharmacological activities counting anti-cancer, anti-inflammatory, immune-modulatory, antileishmanial, anti-ulcer, CNS depressant, anti-fertility, anti-implantation [4, [8][9][10][11][12][13]. RH is an important precursor for the semi-synthetic derivatives flavopiridol and P-276-00.…”

Production of rohitukine in leaves and seeds ofDysoxylum binectariferum: An alternate renewable resource

“…Structural modifications of rohitukine have been explored to enhance its anti-implantation activity (Keshri et al, 2007). It has also been found to attenuate peptic ulcers in rat model (Singh et al, 2012) and exhibits cytotoxic activity against HL-60 promyelocytic leukemia and HCT-116 colon cancer cell lines (Ismail et al, 2009).…”