Pharmacokinetics and antiangiogenic studies of potassium koetjapate in rats.

PURPOSE: Koetjapic acid is an active compound of a traditional medicinal plant, Sandoricum koetjape. Although koetjapic acid has a promising anticancer potential, yet it is highly insoluble in aqueous solutions. To increase aqueous solubility of koetjapic acid, we have previously reported a chemical modification of koetjapic acid to potassium koetjapate (KKA). However, pharmacokinetics of KKA has not been studied. In this study, pharmacokinetics and antiangiogenic efficacy of KKA are investigated. METHODS: Pharmacokinetics of KKA was studied after intravenous and oral administration in SD rats using HPLC. Anti-angiogenic efficacy of KKA was investigated in rat aorta, human endothelial cells (EA.hy926) and nude mice implanted with matrigel. RESULTS: Pharmacokinetic study revealed that KKA was readily absorbed into blood and stayed for a long time in the body with Tmax 2.89 ±â€¯0.12 h, Cmax 7.24 ±â€¯0.36 µg/mL and T1/2 1.46 ±â€¯0.03 h. The pharmacological results showed that KKA significantly suppressed sprouting of microvessels in rat aorta with IC50 18.4 ±â€¯4.2 µM and demonstrated remarkable inhibition of major endothelial functions such as migration, differentiation and VEGF expression in endothelial cells. Further, KKA significantly inhibited vascularization in matrigel plugs implanted in nude mice. CONCLUSIONS: The results indicate that bioabsorption of KKA from oral route was considerably efficient with longer retention in body than compared to that of the intravenous route. Further, improved antiangiogenic activity of KKA was recorded which could probably be due to its increased solubility and bioavailability. The results revealed that KKA inhibits angiogenesis by suppressing endothelial functions and expression of VEGF.

The Anticancer, Antioxidant and Antimicrobial Properties of the Sesquiterpene ß-Caryophyllene from the Essential Oil of Aquilaria crassna.

The present study reports a bioassay-guided isolation of ß-caryophyllene from the essential oil of Aquilaria crassna. The structure of ß-caryophyllene was confirmed using FT-IR, NMR and MS. The antimicrobial effect of ß-caryophyllene was examined using human pathogenic bacterial and fungal strains. Its anti-oxidant properties were evaluated by DPPH and FRAP scavenging assays. The cytotoxicity of ß-caryophyllene was tested against seven human cancer cell lines. The corresponding selectivity index was determined by testing its cytotoxicity on normal cells. The effects of ß-caryophyllene were studied on a series of in vitro antitumor-promoting assays using colon cancer cells. Results showed that ß-caryophyllene demonstrated selective antibacterial activity against S. aureus (MIC 3 ± 1.0 µM) and more pronounced anti-fungal activity than kanamycin. ß-Caryophyllene also displayed strong antioxidant effects. Additionally, ß-caryophyllene exhibited selective anti-proliferative effects against colorectal cancer cells (IC50 19 µM). The results also showed that ß-caryophyllene induces apoptosis via nuclear condensation and fragmentation pathways including disruption of mitochondrial membrane potential. Further, ß-caryophyllene demonstrated potent inhibition against clonogenicity, migration, invasion and spheroid formation in colon cancer cells. These results prompt us to state that ß-caryophyllene is the active principle responsible for the selective anticancer and antimicrobial activities of A. crassnia. ß-Caryophyllene has great potential to be further developed as a promising chemotherapeutic agent against colorectal malignancies.