Cellular Pharmacology of Curcumin With and Without Piperine

Prior reports have suggested that piperine enhances curcumin anti-carcinogenesis. We tested the hypothesis that piperine increases the intracellular concentrations of curcumin by improving intracellular uptake or reducing curcumin efflux or metabolism in breast cells. We incubated SUM149, MCF10A, primary normal human breast cells, ALDH+, and ALDH-CD44+24- SUM149 cells with curcumin with or without piperine at concentrations 1 uM to 15 uM for time periods of 15 minutes to 24 hours. We assayed cell viability by MTT assay and proliferation by primary mammosphere assay. Curcumin and its metabolites were assayed using liquid chromatography mass spectroscopy. Curcumin, but not piperine, showed significantly higher effects on the viability of breast cancer SUM149 cells than in non-tumorigenic MCF10A cells. Curcumin + piperine synergistically reduced viability of SUM149 cells but had a concentration dependent effect upon MCF10A cell viability. Cellular uptake of curcumin in SUM149 is significantly higher, while the efflux in SUM149 is significantly lower than in MCF10A, which correlated with cell viability. Piperine did not alter curcumin cellular uptake, efflux, or metabolism in any of the cell models. The observed synergism of piperine+curcumin in reducing breast stem cell self renewal is likely due to independent anti-carcinogenesis effects rather than any effects upon intracellular curcumin concentrations.

First Nations Healing: From Traditional Medicine to Experimental Ethnopharmacology

Focusing on First Nations traditional medicine, we investigated whether traditional knowledge of medicinal plants can be validated by modern scientific methods of molecular and cellular pharmacology and whether this information is of value for improving current therapy options. Based on two projects on medicinal plants of the Gwich’in – a First Nations group on the Canadian North West Coast – we found that extracts from several plants traditionally used medically were able to kill tumor cells, including otherwise multidrug-resistant cells. Investigating medicinal plants from Indigenous communities raises questions about ownership, appropriation, and commercial use. At the same time, because of the intricacies of patent law, publishing scientific investigations on medicinal herbs represents an effective way to prevent biopiracy. Therefore, research cooperation between industrialized and developing countries, and between Western and non-Western knowledge systems will facilitate ethically sound ethnopharmacological research and merge a diversity of competencies and knowledges.

Pharmacokinetics of tenofovir monoester and association with intracellular tenofovir diphosphate following single-dose tenofovir disoproxil fumarate

Background Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported. Methods Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models. Results Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) Tmax of 0.5 h (0.25–2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0–4 was 93.3 ng·h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng·h/mL (30.0%). Tenofovir monoester AUC0–∞ (but not tenofovir AUC0–∞) was a significant predictor of tenofovir diphosphate in both PBMC (P = 0.015) and DBS (P = 0.005), increasing by 3.8% (95% CI 0.8%–6.8%) and 4.3% (95% CI 1.5%–7.2%), respectively, for every 10 ng·h/mL increase in tenofovir monoester. Conclusions Tenofovir monoester Cmax and AUC0–4 were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.

Cellular Pharmacology of Palladinum(III) Hematoporphyrin IX Complexes: Solution Stability, Antineoplastic and Apoptogenic Activity, DNA Binding, and Processing of DNA-Adducts

Two paramagnetic PdIII complexes of hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp), namely a dinuclear one [PdIII2(Hp-3H)Cl3(H2O)5]·2PdCl2, Pd1 and a mononuclear metalloporphyrin type [PdIII(Hp-2H)Cl(H2O)]·H2O, Pd2 have been synthesized reproducibly and isolated as neutral compounds at different reaction conditions. Their structure and solution stability have been assayed by UV/Vis and EPR spectroscopy. The compounds researched have shown in vitro cell growth inhibitory effects at micromolar concentration against a panel of human tumor cell lines. A DNA fragmentation test in the HL-60 cell line has indicated that Pd1 causes comparable proapoptotic effects with regard to cisplatin but at substantially higher concentrations. Pd1 and cisplatin form intra-strand guanine bis-adducts as the palladium complex is less capable of forming DNA adducts. This demonstrates its cisplatin-dissimilar pharmacological profile. The test for efficient removal of DNA-adducts by the NER synthesis after modification of pBS plasmids with either cisplatin or Pd1 has manifested that the lesions induced by cisplatin are far better recognized and repaired compared those of Pd1. The study on the recognition and binding of the HMGB-1 protein to cisplatin or Pd1 modified DNA probes have shown that HMG proteins are less involved in the palladium agent cytotoxicity.