Abstract
Photodynamic therapy (PDT) and diagnosis (PDD) using 5-aminolevulinic acid (ALA) to drive the production of an intracellular photosensitizer, protoporphyrin IX (PpIX), are in common clinical use. However, the tendency to accumulate PpIX is not well understood. Patients with cancer can develop recurrent metastatic disease with latency periods. This pause can be explained by cancer dormancy. Here we created uniformly sized PC-3 prostate cancer spheroids using a 3D culture plate (EZSPHERE). We demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner not only in spheroids but also in 2D culture. Dormant cancer cells accumulated high PpIX levels and were sensitive to ALA-PDT. In dormant cancer cells, transporter expressions of PEPT1, ALA importer, and ABCB6, an intermediate porphyrin transporter, were upregulated and that of ABCG2, a PpIX exporter, was downregulated. PpIX accumulation and ALA-PDT cytotoxicity were enhanced by G0/G1-phase arrestors in non-dormant cancer cells. Our results demonstrate that ALA-PDT would be an effective approach for dormant cancer cells and can be enhanced by combining with a cell-growth inhibitor.
Highlights
aminolevulinic acid (ALA)-photodynamic diagnosis (PDD) or -PDT are widespread in clinical use, PpIX accumulation mechanism and the difference between high- and low-accumulation cancer cells remain unclear
To investigate the effect of cell dormancy on PpIX accumulation after ALA treatment, we evaluated the accumulation under different cell density conditions in the 2D culture
We demonstrated that PEPT1, ABCB6, and ABCG2 were key players in regulating intracellular PpIX after ALA treatment
Summary
ALA-PDD or -PDT are widespread in clinical use, PpIX accumulation mechanism and the difference between high- and low-accumulation cancer cells remain unclear. In a recent study[12], ABCB6 upregulation played a key role in PpIX accumulation These results suggest that transporters play a critical role in porphyrin metabolism. Patients with cancer can develop a recurrent metastatic disease with latency periods that range from years to even decades[13,14]. This pause can be explained by cancer dormancy[13]. Since Contact inhibition suppresses cell growth[23], cancer spheroids possibly enter the dormant state. We speculated that porphyrin metabolism after cell dormancy and ALA treatment are simultaneously regulated in cancer spheroids in a 3D culture.
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