PubMed · 7260820
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S S Waldenberg. 1981. Koro.. https://doi.org/10.1177/070674378102600228
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Glucose-dependent energy required for glioma metabolism depends on hexokinase, which is mainly bound to mitochondria. A decrease in intracellular pH leads to a release of hexokinase-binding, which in turn decreases glucose phosphorylation, ATP content, and cell proliferation. Thus, intracellular pH might be a target for therapy of gliomas, and a search for agents able to modulate intracellular pH was initiated. Hypericin, a natural photosensitizer, displays numerous biological activities when exposed to light. Its mechanism and site of action at the cellular level remain unclear, but it probably acts by a type II oxygen-dependent photosensitization mechanism producing singlet oxygen. Hypericin is also able to induce a photogenerated intracellular pH drop, which could constitute an alternative mechanism of hypericin action. In human glioma cells treated for 1 h with 2.5 microg/ml hypericin, light exposure induced a fall in intracellular pH. In these conditions, mitochondria-bound hexokinase was inhibited in a light- and dose-dependent manner, associated with a decreased ATP content, a decrease of mitochondrial transmembrane potential, and a depletion of intracellular glutathione. Hexokinase protein was effectively released from mitochondria, as measured by an ELISA using a specific anti-hexokinase antibody. In addition to decreased glutathione, a response to oxidative stress was confirmed by the concomitant increase in mRNA expression of gamma-glutamyl cysteine synthetase, which catalyzes the rate-limiting step in overall glutathione biosynthesis, and is subject to feedback regulation by glutathione. Hypericin also induced a dose- and light-dependent inhibition of [3H]thymidine uptake and induced apoptosis, as demonstrated by annexin V-FITC binding and cell morphology. This study confirmed the mitochondria as a primary target of photodynamic action. The multifaceted action of hypericin involves the alteration of mitochondria-bound hexokinase, initiating a cascade of events that converge to alter the energy metabolism of glioma cells and their survival. In view of the complex mechanism of action of hypericin, further exploration is warranted in a perspective of its clinical application as a potential phototoxic agent in the treatment of glioma tumors.
Telomerase is an attractive target for the design of new anticancer drugs. We have previously described a series of 1,4- and 2, 6-difunctionalized amidoanthracene-9,10-diones that inhibit human telomerase via stabilization of telomeric G-quadruplex structures. The present study details the preparation of three further, distinct series of regioisomeric difunctionalized amidoanthracene-9,10-diones substituted at the 1,5-, 1,8-, and 2,7-positions, respectively. Their in vitro cytotoxicity and Taq DNA polymerase and human telomerase inhibition properties are reported and compared with those of their 1,4- and 2,6-isomers. Potent telomerase inhibition (telIC50 values 1.3-17.3 microM) is exhibited within each isomeric series. In addition, biophysical and molecular modeling studies have been conducted to examine binding to the target G-quadruplex structure formed by the folding of telomeric DNA. These studies indicate that the isomeric diamidoanthracene-9,10-diones bind to the human telomeric G-quadruplex structure with a stoichiometry of 1:1. Plausible G-quadruplex-ligand complexes have been identified for each isomeric family, with three distinct modes of intercalative binding being proposed. The exact mode of intercalative binding is dictated by the positional placement of substituent side chains. Furthermore, in contrast to previous studies directed toward triplex DNA, it is evident that stringent control over positional attachment of substituents is not a necessity for effective telomerase inhibition.
1. Whole-cell currents and intracellular Ca2+ concentration ([Ca2+]i) were recorded in cultured human aortic endothelial cells (HAECs) to study the mechanisms underlying Cl--sensitive Ca2+ entry. 2. In the absence of histamine the membrane potential ranged between -90 and +5 mV and showed bimodal distribution with peaks at -17.8 and -67.5 mV. 3. Histamine (1-100 microM) activated an outward current, followed by a sustained inward current at -50 mV. The reversal potential (Vrev) was more negative than -60 mV for the initial outward current, and approximately -30 mV for the sustained inward current with normal Tyrode solution and internal solution containing 30 mM Cl-. 4. Vrev of the sustained inward current was hardly affected by varying the external concentrations of K+, Na+ and Ca2+, but was greatly changed by varying the external Cl- concentration ([Cl-]o). The relationship between Vrev and log[Cl-]o showed a slope of -44.8 mV per tenfold increase of [Cl-]o. 5. The Cl- channel blockers 9-anthracene carboxylic acid (1 mM), N-phenylanthranilic acid (0.1 mM) and niflumic acid (0.1 mM) all depressed the histamine-induced inward current. The non-selective cation channel blocker Gd3+ (10 microM) was without effect on the current. 6. In the absence of histamine, [Ca2+]i was not affected by varying the membrane potential. During the continuous presence of histamine, however, hyperpolarization increased and depolarization decreased [Ca2+]i, indicating that Ca2+ entry through the plasma membrane was activated by histamine. 7. Vrev of the histamine-induced Cl- current, measured by the gramicidin-perforated patch clamp method, was -28.4 +/- 6.6 mV (n = 8), which gave an intracellular Cl- concentration of approximately 34 mM. Under the current clamp condition, the membrane potential varied from cell to cell in the control, but application of histamine induced either depolarization or hyperpolarization, depending on the membrane potential before histamine application, and the membrane potential became stable near the equilibrium potential for Cl-. 8. We conclude that the histamine-induced inward current is carried mainly by Cl-. Although Ca2+ entry was also activated, we consider that its amplitude was too small to be resolved by the patch clamp method. The Cl- current may play a functional role in the sustained [Ca2+]i elevation by providing a constant driving force for Ca2+ entry in the presence of histamine.