hyperforin and Leukemia

The acylphloroglucinols hyperforin (Hypf) and myrtucommulone A (MC A) induce death of cancer cells by triggering the intrinsic/mitochondrial pathway of apoptosis, accompanied by a loss of the mitochondrial membrane potential and release of cytochrome c. However, the upstream targets and mechanisms leading to these mitochondrial events in cancer cells remain elusive. Here we show that Hypf and MC A directly act on mitochondria derived from human leukemic HL-60 cells and thus, disrupt mitochondrial functions. In isolated mitochondria, Hypf and MC A efficiently impaired mitochondrial viability (EC50 = 0.2 and 0.9 µM, respectively), caused loss of the mitochondrial membrane potential (at 0.03 and 0.1 µM, respectively), and suppressed mitochondrial ATP synthesis (IC50 = 0.2 and 0.5 µM, respectively). Consequently, the compounds activated the adenosine monophosphate-activated protein kinase (AMPK) in HL-60 cells, a cellular energy sensor involved in apoptosis of cancer cells. Side by side comparison with the protonophore CCCP and the ATP synthase inhibitor oligomycin suggest that Hypf and MC A act as protonophores that primarily dissipate the mitochondrial membrane potential by direct interaction with the mitochondrial membrane. Together, Hypf and MC A abolish the mitochondrial proton motive force that on one hand impairs mitochondrial viability and on the other cause activation of AMPK due to lowered ATP levels which may further facilitate the intrinsic mitochondrial pathway of apoptosis.

Topics: Adenosine Triphosphate; AMP-Activated Protein Kinases; Apoptosis; HL-60 Cells; Humans; Leukemia; Membrane Potential, Mitochondrial; Mitochondria; Phloroglucinol; Terpenes

Recent data suggest some relevant drug interactions caused by St John's wort extract, which can be explained by interactions with the Cytochrome P450 system or P-Glycoprotein (Pgp). Interaction with Pgp, including activation, inhibition and induction, can lead to altered plasma or brain levels of Pgp substrates. The aim of the present study was to investigate the possible interactions of St John's wort extract and most relevant constituents with the transport activity of Pgp.. We characterized the modulatory potencies in two in vitro assays using calcein-AM, first in VLB cells (a human lymphocytic leukemia cell line expressing Pgp) and second in PBCEC cells (porcine brain capillary endothelial cells).. The extract, as well as some of the tested constituents modulate the transport by Pgp in the micromolecular range. Quercetin and hyperforin seem to be most potent.. These findings suggest the possibility of drug interactions at the level of the gastro-intestinal absorption of drugs. Plasma levels of the constituents of St John's wort are very likely too low to interfere with Pgp at the blood-brain-barrier with the possible exception of quercetin.

Topics: Adenosine Triphosphate; Amitriptyline; Animals; Antidepressive Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain; Bridged Bicyclo Compounds; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; Endothelial Cells; Fluoresceins; Fluoxetine; Herb-Drug Interactions; Humans; Hypericum; Leukemia; Models, Biological; Phloroglucinol; Plant Extracts; Quercetin; Swine; Terpenes