Modulation of Hypericin Photodynamic Therapy by Pretreatment with 12 Various Inhibitors of Arachidonic Acid Metabolism in Colon Adenocarcinoma HT‐29 Cells

Abstract

One proposal to increase the efficiency of photodynamic therapy (PDT) is to accompany photosensitization with other treatment modalities, including modulation of arachidonic acid (AA) metabolism. The aim of this study was to evaluate the effectiveness of a combined modality approach employing 48 and 24 h pretreatment with various inhibitors of lipoxygenase (LOX; nordihydroguaiaretic acid, esculetin, AA-861, MK-886 and baicalein), cyclooxygenase (COX; diclofenac, flurbiprofen, ibuprofen, indomethacin, SC-560 and rofecoxib) and cytochrome P450-monooxygenase (proadifen) pathways, followed by hypericin-mediated PDT. Cytokinetic parameters like MTT assay, adherent and floating cell numbers, viability and cell cycle distribution analysis were examined 24 h after hypericin activation. Pretreatment of human colon cancer cells HT-29 prior to PDT with 5-LOX inhibitor MK-886 as well as 5, 12-LOX and 12-LOX inhibitors (esculetin and baicalein, respectively) resulted in significant and dose-dependent effects on all parameters tested. Pretreatment with diclofenac, flurbiprofen, ibuprofen and indomethacin, the nonspecific COX inhibitors, promoted hypericin-mediated PDT, but these effects were probably COX-independent. In contrast, application of SC-560 and rofecoxib, specific inhibitors of COX-1 and COX-2, respectively, attenuated PDT. Inhibition of P450 monooxygenase with proadifen implied also the significance of this metabolic pathway in cell survival and cell resistance to hypericin photocytotoxicity. In conclusion, our results testify that application of diverse inhibitors of AA metabolism may have different consequences on cellular response to hypericin-mediated PDT and that some of them could be considered for potentiation of PDT.

Potency of non-steroidal anti-inflammatory drugs in chemotherapy

“…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). An important role for the MRP1 and BCRP transporters in HY efflux was also demonstrated (119).…”

“…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).…”

Memory Encoded Throughout Our Bodies: Molecular and Cellular Basis of Tissue Regeneration

“…Resolving this puzzle seems to be one of the keys to understanding and the treatment of skin aging and photodamage, as well as to development of the best practices for suntanning. In clinical practice, unavoidable vascular damage is often created during actinic, cytostatic or surgical therapy of tumors, and thus, development of gentle and specific tumoricidal therapies like targeted photodynamic approaches may help spare the normal tissue of oncology patients (134). Although in some other oncological strategies there has been a considerable effort made toward inhibition and/or destruction of blood vessels to devitalize tumor tissues (135), the opposite effort is usually exercised in tissue engineering and wound healing research (136,137) to keep regenerating or engineered tissues alive and functional.…”

Potentiation of hypericin-mediated photodynamic therapy cytotoxicity by MK-886: Focus on ABC transporters, GDF-15 and redox status

“…Combinations of multiple therapeutic modalities can provide a broader range of coverage against resistant tumour cells, and allows the use of individual drugs at lower doses, reducing toxic side-effects, as already proved in clinical practice. PDT efficacy can be potentiated through multiple mechanisms, including combination with antibiotics [37] and antioxidant inhibitors [38], conjugation with nanocarrier systems [39] and pretreatment with various AA metabolism inhibitors [40]. We already proved that MK-886 increases sensitivity of tumour cells to HY-PDT [19,20,40].…”

“…PDT efficacy can be potentiated through multiple mechanisms, including combination with antibiotics [37] and antioxidant inhibitors [38], conjugation with nanocarrier systems [39] and pretreatment with various AA metabolism inhibitors [40]. We already proved that MK-886 increases sensitivity of tumour cells to HY-PDT [19,20,40]. It is also able to potentiate the efficacy of other treatments, for example, chemopreventive and antitumour effects of other NSAIDs [23,41], augmenting differentiation of leukaemic cells induced by 1α,25-dihydroxyvitamin D 3 [42] and contributing to a reduction of TRAIL-resistance in glioma cells [43].…”