Phototoxic and Apoptosis-Inducing Capacity of Pseudohypericin

Abstract

Pseudohypericin (PH) and hypericin (H) are photosensitizing plant pigments from Hypericum perforatum. H displays cytotoxic and apoptosis-inducing effects in neoplastic cell lines. Here, we have assessed the phototoxic and apoptosis-inducing capacity of PH compared to H in a cell culture model with human leukemic lymphoma cells (Jurkat). Treatment with both photoactivated H and PH resulted in a dose-dependent inhibition of cell proliferation, whereas not photoactivated H and PH had no effect at the concentrations tested. The half-maximal inhibitory concentration (IC₅₀) of H was lower (100 ng/mL) as compared to PH (200 ng/mL) (p < 0.05). In an apoptosis assay we found a dose-dependent increase of DNA fragmentation after treatment with both photoactivated H and PH. The cytotoxic potential of PH should be taken into account during systemic therapy with Hypericum extracts, since PH is about two times more abundant than H in Hypericum perforatum.

References

• 1 Duran N, Song P S. Hypericin and its photodynamic action.  Photochem Photobiol. 1986;  43 677-80
• 2 Vandenbogaerde A L, Delaey E M, Vantieghem A M, Himpens B E, Merlevede W J, de Witte P A. Cytotoxicity and antiproliferative effect of hypericin and derivatives after photosensitization.  Photochem Photobiol. 1998;  67 119-25
• 3 Koren H, Schenk G M, Jindra R H, Alth G, Ebermann R, Kubin A, Konderhold G, Kreitner M. Hypericin in phototherapy.  J Photochem Photobiol (B). 1996;  36 13-9
• 4 Thomas C, Randall S, MacGill S, Miller G C, Pardini R S. Photoactivation of hypericin generates singlet oxygen in mitochondria and inhibits succinyloxidase.  Photochem Photobiol. 1992;  55 47-53
• 5 Utsumi T, Okuma M, Utsumi T, Kanno T, Yasuda T, Kobuchi H, Horton H H, Utsumi K. Light-dependent inhibition of protein kinase C and superoxide generation of neutrophils by hypericin, an antiretroviral agent.  Arch Biochem Biophys. 1995;  316 493-7
• 6 Agostinis P, Donella-Deana A, Cuveele J, Vandenbogaerde A, Sarno S, Merlevede W, de Witte P. A comparative analysis of the photosensitized inhibition of growth-factor regulated protein kinases by hypericin-derivates.  Biochem Biophys Res Comm. 1996;  220 613-7
• 7 de Witte P, Agostinis P, van Lint J, Merlevede W, Fandenheede J R. Inhibition of epidermal growth factor receptor tyrosine kinase activity by hypericin.  Biochem Pharmacol. 1993;  46 1929-36
• 8 Kil K S, Yum Y N, Seo S H, Lee K T. Antitumor activities of hypericin as a protein tyrosine kinase blocker.  Arch Pharmacol Res. 1996;  19 490-6
• 9 Bork P M, Bacher S, Schmitz M L, Kaspers U, Heinrich M. Hypericin as a non-antioxidant inhibitor of NF-κB.  Planta Med. 1999;  65 297-300
• 10 Schempp C M, Simon-Haarhaus , Termeer C C, Simon J C. Hypericin photo-induced apoptosis of Jurkat cells involves the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and activation of caspase-8.  FEBS Lett. 2001;  493 6-30
• 11 Roth L. Hypericum - hypericin. Landsberg/Lech, Germany; Ecomed 1990
• 12 Kerb R, Brockmöller J, Staffeldt B, Ploch M, Roots I. Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin.  Antimicrob Ag Chemother. 1996;  40 2087-93
• 13 Brockmöller J, Reum T, Bauer S, Kerb R, Hübner W D, Roots I. Hypericin and pseudohypericin: pharmacokinetics and effects on photosensitivity in humans.  Pharmacopsychiatry. 1997;  30 56-63
• 14 Schempp C M, Winghofer B, Schöpf E, Simon J C. Hypericin and pseudohypericin levels in human serum and skin blister fluid after systemic application of Hypericum perforatum extract (St. John’s Wort).  Skin Pharmacol. 1999;  12 299-304
• 15 Vandenbogaerde A L, Kamuhabwa A, Delaey E, Himpens B E, Merlevede W J, de Witte P A. Photocytotoxic effect of pseudohypericin versus hypericin.  J Photochem Photobiol B.. 1998;  45 87-94
• 16 Butterweck V, Petereit F, Winterhoff H, Nahrstedt A. Solubilized hypericin and pseudohypericin from Hypericum perforatum exert antidepressant activity in the forced swimming test.  Planta Med. 1998;  64 91-4
• 17 Schempp C M, Simon-Haarhaus B, Heine A, Schöpf E, Simon J C. In vitro and in vivo activation of hypericin with the incoherent light source PDT 1200 SOA (520 - 750 nm) and with solar simulated radiation (290 - 2500 nm).  Photodermatol Photoimmunol Photomed. 1999;  5 13-7