St. John's wort and its constituent hyperforin concordantly regulate expression of genes encoding enzymes involved in basic cellular pathways

BACKGROUND: Meso-tetra-hydroxyphenyl-chlorine (mTHPC) is among the most powerful photosensitizers available for photodynamic therapy (PDT). However, the mechanisms leading to cell death are poorly understood. We here focused on changes at DNA and RNA levels after treatment with the liposomal mTHPC derivative Foslipos in vitro. METHODS: After determination of darktoxicity, laser conditions and uptake kinetics, PC-3 prostate carcinoma cells were subjected to PDT with Foslipos, followed by assessment of cell numbers directly (TP0) or 1h (TP1), 2h (TP2), 5h (TP5) and 24h (TP24) after illumination. Nucleic acids had been extracted for evaluation of RNA amounts and integrity as well as for estimation of abasic sites as a measure for DNA damage. Furthermore, expression changes of 84 genes related to oxidative stress were investigated by quantitative polymerase chain reaction. RESULTS: Already at TP0, the number of dead cells was significantly higher after PDT versus controls and at TP24 more than 90% of cells had been destroyed. PDT resulted in a severe damage of both RNA and DNA. Gene expression analyses revealed an impact of PDT on pathways for oxidative and metabolic stress, heat shock, proliferation and carcinogenesis, growth arrest, inflammation, DNA repair and apoptosis signaling. CONCLUSIONS: Mechanisms of Foslipos-mediated PDT comprise a combination of acute and delayed lethal effects in PC-3 cells. The latter may include death processes initiated by nucleic acid damage, activation of stress and growth arrest genes in combination with a reduced capability to adequately cope with oxidative toxicity. Our results will help to better understand molecular photodynamic effects. AbstractBackground: Meso-tetra-hydroxyphenyl-chlorine (mTHPC) is among the most powerful

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“…PDT with other photosensitizers are partly in accordance [35,36] and partly in contrast to our data [37,38]. Because CAT and SOD1…”

Section: Discussioncontrasting

confidence: 54%

Cellular and molecular effects of the liposomal mTHPC derivative Foslipos in prostate carcinoma cells in vitro

Gyenge

Hiestand

Graefe

et al. 2011

Photodiagnosis and Photodynamic Therapy

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“…For example, the herbal medicine St. John's Wort is a strong inducer of several human drug-metabolizing enzymes (Delgoda and Westlake 2004) but also induces MRP2 transcription in rats and in human HepG2 cells respectively (Shibayama et al 2004;Krusekopf and Roots 2005). Via the same PXRmediated transactivation, human CYP3A4 and P-glycoprotein expression is enhanced, too (Synold et al 2001).…”

Section: Clinical Importance Of Implementing Drug Transporter Phasesmentioning

confidence: 99%

Drug transporters in pharmacokinetics

Petzinger¹,

Geyer²

2006

Naunyn Schmied Arch Pharmacol

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This review deals with the drug transporters allowing drugs to enter and leave cells by carrier-mediated pathways. Emphasis is put on liver transporters but systems in gut, kidney, and blood-brain barrier are mentioned as well. Drug-drug interactions on carriers may provoke significant modification in pharmacokinetics as do carrier gene polymorphisms yielding functional carrier protein mutations. An integrated phase concept should reflect the interplay between drug metabolism and drug transport.

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“…76 Another major concern for HF pharmacological use resides in its potential interference with other drugs through its activating effect on various CYP450, notably CYP3A4. 77 The design of HF analogs retaining the pharmacological properties of the parental compound, but unable to stimulate expression of CYP3A4 will be a challenge for the pharmacochemists in the near future.…”

Section: Discussionmentioning

confidence: 99%

Hyperforin, a new lead compound against the progression of cancer and leukemia?

Quiney

Billard

Salanoubat³

et al. 2006

Leukemia

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St. John's wort and its constituent hyperforin concordantly regulate expression of genes encoding enzymes involved in basic cellular pathways

Abstract: St. John's wort and hyperforin concordantly affected expression of genes not only mediating metabolism and transport of exogenous and endogenous compounds, but also involved in energy metabolism, intracellular calcium regulation, cell proliferation and apoptosis.

Cited by 39 publications

References 61 publications

Cellular and molecular effects of the liposomal mTHPC derivative Foslipos in prostate carcinoma cells in vitro

Cellular and molecular effects of the liposomal mTHPC derivative Foslipos in prostate carcinoma cells in vitro

Drug transporters in pharmacokinetics

Hyperforin, a new lead compound against the progression of cancer and leukemia?

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