Drug membrane transporters and CYP3A4 are affected by hypericin, hyperforin or aristoforin in colon adenocarcinoma cells.
Our previous results have shown that the combination of hypericin-mediated photodynamic therapy (HY-PDT) at sub-optimal dose with hyperforin (HP) (compounds of Hypericum sp.), or its stable derivative aristoforin (AR) stimulates generation of reactive oxygen species (ROS) leading to antitumour activity. This enhanced oxidative stress evoked the need for an explanation for HY accumulation in colon cancer cells pretreated with HP or AR. Generally, the therapeutic efficacy of chemotherapeutics is limited by drug resistance related to the overexpression of drug efflux transporters in tumour cells. Therefore, the impact of non-activated hypericin (HY), HY-PDT, HP and AR on cell membrane transporter systems (Multidrug resistance-associated protein 1-MRP1/ABCC1, Multidrug resistance-associated protein 2-MRP2/ABCC2, Breast cancer resistance protein - BCRP/ABCG2, P-glycoprotein-P-gp/ABCC1) and cytochrome P450 3A4 (CYP3A4) was evaluated. The different effects of the three compounds on their expression, protein level and activity was determined under specific PDT light (T0+, T6+) or dark conditions (T0- T6-). We found that HP or AR treatment affected the protein levels of MRP2 and P-gp, whereas HP decreased MRP2 and P-gp expression mostly in the T0+ and T6+ conditions, while AR decreased MRP2 in T0- and T6+. Moreover, HY-PDT treatment induced the expression of MRP1. Our data demonstrate that HP or AR treatment in light or dark PDT conditions had an inhibitory effect on the activity of individual membrane transport proteins and significantly decreased CYP3A4 activity in HT-29 cells. We found that HP or AR significantly affected intracellular accumulation of HY in HT-29 colon adenocarcinoma cells. These results suggest that HY, HP and AR might affect the efficiency of anti-cancer drugs, through interaction with membrane transporters and CYP3A4.
Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia. Electronic address: martina.semelakova@upjs.sk.
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Šemeláková
Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia.
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Jendželovský
Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Moyzesova 11, 040 01 Košice, Slovakia.
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Fedoročko
D000230:Adenocarcinoma / Q000235:genetics*; D000873:Anthracenes; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D049454:Firefly Luciferin / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology; D010696:Phloroglucinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D013729:Terpenes / Q000494:pharmacology*
C000715087:ABCC2 protein, human; D000873:Anthracenes; C502222:Aristoforin; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins; D013729:Terpenes; D010569:Perylene; D049454:Firefly Luciferin; C004965:hypericin; D010696:Phloroglucinol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C001654:hyperforin
Aristoforin; CYP3A4; Drug efflux; Drug resistance; Hyperforin; Hypericin