Drug efflux transporters, MRP1 and BCRP, affect the outcome of hypericin-mediated photodynamic therapy in HT-29 adenocarcinoma cells

Abstract

Photodynamic therapy (PDT) is a flexible multi-target therapeutic approach. One of the main requirements of successful PDT is sufficient intracellular concentration of an applicable photosensitizer. Mechanisms of anticancer drug elimination by tumour cells are mostly linked to the elevated expression and activity of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and P450 monooxygenases. The interaction of hypericin with this cell drug-defence system is still unclear. We report here for the first time increased activity of MRP1 and BCRP in HT-29 colon cancer cells treated with hypericin per se. On the contrary, pre-treatment with proadifen (SKF525A) affected the function of MRP1 and BCRP leading to increased hypericin content, which might indicate a possible link between proadifen and these ABC transporter proteins. Subsequent enhanced intracellular oxidative stress was accompanied by loss of mitochondrial membrane potential, activation of caspase-9 and -3, PARP cleavage and onset of apoptosis. In conclusion, our study suggests that drug efflux transporters MRP1 and BCRP affect the pharmacokinetics of hypericin in HT-29 colon adenocarcinoma cells, and the action of hypericin-mediated PDT (HY-PDT) should be modulated by pre-treatment with their specific inhibitors.

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

“…The specific inhibition of COX, LOX and CYP450 activity increased the efficacy of HY-PDT in the HT-29 cancer cell line (121). An important role for the MRP1 and BCRP transporters in HY efflux was also demonstrated (119). Proadifen, a P450 monooxygenase inhibitor, was shown to inhibit these transport proteins, resulting in a significant increase in intracellular HY accumulation in HT-29 cells and MRP1 and BCRP-overexpressing cells.…”

“…COX-2 was found to be involved in the regulation of P-gp, MRP1 and BCRP transporter expression via the COX-2/PGE2̸PGE receptor 4̸phosphatidyl inositol 3-kinase pathway (116,118). Synergistic effects of NSAIDs with hypericin (HY)-mediated photodynamic therapy (PDT) have also been reported (119)(120)(121)(122). The specific inhibition of COX, LOX and CYP450 activity increased the efficacy of HY-PDT in the HT-29 cancer cell line (121).…”

Photodynamic therapy of cancer — Challenges of multidrug resistance

“…39 Jendzelovský et al showed that Proadifen, an inhibitor of cytochrome P450 enzymes, could a®ect the function of BCRP and MRP1 leading to increased hypericin content in colon cancer cells (HT-29 cells). 40 BCRP-mediated PpIX e®lux was also a major factor that prevented PpIX accumulation in human urothelial carcinoma cells (T24 cells). 41 Bebes et al showed that the PpIX extrusion ability of keratinocytes (HaCaT cells) was correlated with their BCRP expression which was higher in proliferating cells than in di®erentiated cells.…”

Alterations in dysadherin expression and F-actin reorganization: a possible mechanism of hypericin-mediated photodynamic therapy in colon adenocarcinoma cells

“…In order to measure the intensity of HYP fluorescence in the cells CellQuestPro software was used. HYP content was evaluated as mean fluorescence intensity (MFI) and as the ratio of MFI in treatment/control group (relative fluorescence intensity, RFI) (Jendzelovsky et al 2009). …”