Single-dose comparative pharmacokinetic/pharmacodynamic study of a micellar formulation versus a native Boswellia serrata dry extract in healthy volunteers.

BACKGROUND: Extracts of oleogum resins of Boswellia trees possess anti-inflammatory activities. Micellar formulations have been developed to increase the oral bioavailability of bioactive boswellic and lupeolic acids. PURPOSE: The current single-dose crossover clinical trial compares for the first time pharmacokinetics/pharmacodynamics of two Boswellia serrata nutraceuticals, native Biotikon® BS-85 and micellar Boswellia-Loges®. METHODS: After oral administration of the study preparations (800 mg) to 20 healthy volunteers, plasma concentrations of 8 boswellic and lupeolic acids were measured by using HPLC-MS/MS for up to 48 h Blood samples collected 2 and 5 h after drug administration were stimulated for 24 h with endotoxic lipopolysaccharide. The release of proinflammatory cytokines analyzed by flow cytometry was used as readout of the pharmacodynamic properties of the preparations. REGISTRATION: German Clinical Trials Register (DRKS) No. DRKS00027369. RESULTS: Administration of the micellar extract significantly increased Cmax, AUC0-48, and shortened Tmax for all boswellic and lupeolic acids compared to native extract. Accordingly, their relative bioavailability increased to 1,720-4,291 % with the highest difference for acetyl-11-keto-ß-boswellic acid (AKBA). Both preparations reduced the release of TNF-α and the native formulation diminished also IL-1ß and IL-6. However, no significant differences were observed between the preparations, except for a higher decrease in IL-1ß by the native formulation Biotikon® BS-85. In a lymphocytic gene reporter cell line, both nutraceuticals similarly inhibited the NF-κB transcription factor activity as well as the TNF-α release, yet the native formulation Biotikon®BS-85 was more efficient in inhibiting TNF-α. CONCLUSION: Administration of the micellar Boswellia serrata nutraceutical increased the oral bioavailability of boswellic and lupeolic acids. Yet, the increase in plasma concentration did not enhance the anti-inflammatory efficacy of the micellar extract compared to the native extract in this ex vivo model.

Prenylated xanthones from mangosteen (Garcinia mangostana) target oxidative mitochondrial respiration in cancer cells.

Mangosteen (Garcinia mangostana) is well-known for its nutritional value and health benefits. Breast cancer is the most common cancer and the leading cause of cancer-related mortality among females worldwide. Here we show that the prenylated xanthones, α-mangostin, γ-mangostin, 9-hydroxycalabaxanthone (9-HCX), and garcinone E from the mangosteen pericarp exhibit cytotoxicity against a panel of human cancer cell lines including lung adenocarcinoma (A549), cervical carcinoma (HeLa), prostatic carcinoma (DU 145), pancreatic carcinoma (MIA PaCa-2), hepatocellular carcinoma (Hep G2), bladder urothelial cancer (5637), as well as the triple-negative breast cancer cells MDA-MB-231. In line with its higher predicted bioactivity score compared to other prenylated xanthones, 9-HCX induced the strongest antiproliferative and proapoptotic effects in MDA-MB-231 breast cancer xenografts in vivo. In different in vitro models, we demonstrate that prenylated xanthones from G. mangostana target mitochondria in cancer cells by inhibition of the mitochondrial respiratory chain complex II (α-mangostin, γ-mangostin, and garcinone E) and complex III (9-HCX) as shown in isolated mitochondria. Accordingly, oxidative mitochondrial respiration (OXPHOS) was inhibited, mitochondrial proton leak increased, and adenosine triphosphate (ATP) synthesis decreased as analyzed by Seahorse assay in MDA-MB-231 cells. Hence, the prenylated xanthones increased mitochondrial superoxide levels, induced mitochondrial membrane permeabilization, and initiated caspase 3/7-mediated apoptosis in MDA-MB-231 triple-negative breast cancer cells. Thus, prenylated xanthones from Garcinia mangostana exhibit anticancer activity based on interference with the mitochondrial respiration.

The SC cell line as an in vitro model of human monocytes.

In vitro analysis of human macrophages is generally hampered by the necessity to differentiate them from peripheral blood monocytes. We have analyzed to which extent noncancerous SC monocytes could be used as an in vitro macrophage model. Macrophages differentiated from peripheral monocytes using standard CSF1 and CSF2 protocols for M2 and M1 precursors, respectively, were compared with THP-1-derived macrophages treated with PMA and with SC-derived macrophages differentiated either by CSF1, CSF2, or PMA according to different protocols. The optimal condition for generation of SC macrophages was treatment with PMA for 3 days, followed by 5-days culture without PMA and 24-h polarization with LPS/IFN-γ or IL-4/IL-13. Similar to THP-1, SC cells do not express the monocyte marker CD14 and differentiation to macrophages results neither in CD68 nor in CD14 expression, both of which were expressed by monocyte-derived macrophages. Similar to THP-1-macrophages, a proportion of SC macrophages can be polarized to the M1-like subtype that is characterized by higher expression of CD38, CD86, CD80, TNF-α, and IL-1ra, whereas treatment with IL4/IL13 did not lead to expression of the M2-associated receptors CD163, CD206, and only slightly increased the CD200R expression. Still, SC-M1 express much lower levels of the M1-associated markers compared with monocyte-derived M1 and no IL-1ß. The data demonstrate that SC-derived macrophages differ from monocyte-derived macrophages in respect of their morphology, expression of important macrophage markers, phagocytosis. Yet, polarized SC-M1-like cells may with restrictions serve as a model for M1 macrophages, though this model does not provide significant advantages over already well-described THP-1-M1-like cells.