Tetraacetyl riboflavin derivative mediates caspase 3/7 activation via MAPK in A431 cells upon blue light influence

Abstract

An acetylated riboflavin derivative, 3‐methyl‐tetraacetyl riboflavin (3MeTARF), is a compound with high photostability and photophysical properties similar to riboflavin, including the ability to photogenerate singlet oxygen. In the present study, we compared the effects of irradiation on A431 cancer cells with blue LED light (438 nm) in the presence of 3MeTARF and riboflavin on MAPK phosphorylation, apoptosis, caspase 3/7 activation and PARP cleavage. We observed that photogenerated oxidative stress in this reaction activates MAPK by increasing phosphorylation of p38 and JNK proteins. Preincubation of cells with inhibitors specific for phosphorylation of p38 and JNK proteins (SB203580, SP600125), respectively, results in decreased caspase 3/7 activation and PARP cleavage. We showed that the tetraacetyl derivative more effectively activates MAPK and skin cancer cell death compared to riboflavin. These data, together with results of our previous study, support the hypothesis that 3MeTARF, of riboflavin, might be more useful and desirable as a compound for use in photodynamic oxidation processes, including its therapeutic potential.

Riboflavin and Its Derivates as Potential Photosensitizers in the Photodynamic Treatment of Skin Cancers

“…Our recent in vitro studies confirmed that 3MeTARF induces apoptosis of WM115 melanoma and A431 human epidermal cancer cells under blue light, while the percentage of necrotic cells did not exceed 6% [ 34 , 85 ].…”

“…The antimicrobial activity of riboflavin on its own and in combination with UVA is widely described in the review by Farah et al [84]. [34,43,[84][85][86][87]].…”

“…The main types of non-melanoma skin cancer are basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC) [92], while melanomas include superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma (NM) [91]. [34,43,[84][85][86][87]].…”

“…In fact, 3MeTARF induces oxidative stress and cell death in skin cancer (A431) and melanoma cells (WM115) [ 34 , 85 ], and also kills the parasite Leishmania major more effectively than riboflavin [ 43 ]. Interestingly, lumichrome, the product of light-induced or enzymatic degradation of riboflavin, appeared to be selective towards bacteria, being ten times more effective against Gram-positive bacteria than against Gram-negative bacteria [ 87 ].…”

“…It has been demonstrated that pre-incubation of A431 cells with inhibitors specific for protein phosphorylation of p38 and JNK (SB203580, SP600125, respectively) results in decreased caspase 3/7 activation and PARP cleavage [ 34 , 85 ]. Since the phototoxic effect of 3MeTARF was five to ten times more pronounced, when compared to riboflavin, it again support the hypothesis that riboflavin’s analogue 3MeTARF may be more useful and desirable as an agent for use in photodynamic oxidation processes, including its therapeutic potential.…”