Conventional
photodynamic therapy with aminolevulinate (ALA-
PDT) selectively induces apoptosis in diseased cells and is highly effective for treating
actinic keratoses. However, similar results are achieved only in a subset of patients with
cutaneous T-cell lymphoma (CTCL). Our previous work shows that the apoptotic resistance of CTCL correlates with low expression of
death receptors like
Fas cell surface death receptor (FAS), and that
methotrexate upregulates FAS by inhibiting the methylation of its promoter, acting as an epigenetic derepressor that restores the susceptibility of FAS-low CTCL to caspase-8-mediated apoptosis. Here, we demonstrate that
methotrexate increases the response of CTCL to ALA-
PDT, a concept we refer to as epigenetically enhanced
PDT (ePDT). Multiple CTCL cell lines were subjected to conventional
PDT versus ePDT. Apoptotic
biomarkers were analyzed in situ with multispectral imaging analysis of immunostained cells, a method that is quantitative and 5× more sensitive than standard immunohistology for
antigen detection. Compared to conventional
PDT or
methotrexate alone, ePDT led to significantly greater cell death in all CTCL cell lines tested by inducing greater activation of caspase-8-mediated extrinsic apoptosis. Upregulation of FAS and/or
tumor necrosis factor-related apoptosis-inducing
ligand pathway components was observed in different CTCL cell lines. These findings provide a rationale for clinical trials of ePDT for CTCL.