Dormant cancer cells accumulate high protoporphyrin IX levels and are sensitive to 5-aminolevulinic acid-based photodynamic therapy

摘要

Photodynamic therapy (PDT) and diagnosis (PDD) using 5-aminolevulinic acid (ALA) to drive the production of anintracellular photosensitizer, protoporphyrin IX (PpIX), are in common clinical use. However, the tendency toaccumulate PpIX is not well understood. Patients with cancer can develop recurrent metastatic disease with latencyperiods. This pause can be explained by cancer dormancy. Here we created uniformly sized PC-3 prostate cancerspheroids using a 3D culture plate (EZSPHERE). We demonstrated that cancer cells exhibited dormancy in a celldensity-dependent manner not only in spheroids but also in 2D culture. Dormant cancer cells accumulated high PpIXlevels and were sensitive to ALA-PDT. In dormant cancer cells, transporter expressions of PEPT1, ALA importer, andABCB6, an intermediate porphyrin transporter, were upregulated and that of ABCG2, a PpIX exporter, wasdownregulated. PpIX accumulation and ALA-PDT cytotoxicity were enhanced by G0/G1-phase arrestors in nondormantcancer cells. Our results demonstrate that ALA-PDT would be an effective approach for dormant cancer cellsand can be enhanced by combining with a cell-growth inhibitor.