Enhanced accumulation of protoporphyrin IX via SLC6A6 and SLC36A1 sensitizes cisplatin-resistant cells to 5-aminolevulinic acid-based photodynamic therapy.

Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is a promising treatment for cancer cells. Although cisplatin (CDDP) is a potent anticancer drug, acquired resistance often limits its clinical efficacy. This study aimed to evaluate the effectiveness of 5-ALA-PDT in CDDP-resistant cancer cells and elucidate the underlying mechanisms. We used CDDP-resistant sublines (ACR20 and HCR5) derived from human lung cancer (A549) and cervical epithelioid carcinoma (HeLa) cells, respectively. Intracellular protoporphyrin IX (PpIX) accumulation, mRNA expression of transporters and heme synthesis enzymes, and phototoxicity were analyzed. Both CDDP-resistant sublines exhibited significantly higher sensitivity to 5-ALA-PDT and increased intracellular PpIX accumulation compared to their respective parental cells. The mRNA expression of the 5-ALA transporters, SLC6A6 and SLC36A1, was significantly upregulated in both CDDP-resistant sublines. Treatment with their inhibitors (guanidinoethyl sulfonate for SLC6A6 and tryptophan for SLC36A1) markedly reduced PpIX accumulation and cytotoxic effects of 5-ALA-PDT. Although protoporphyrinogen oxidase expression was elevated in ACR20 cells, 5-ALA-PDT cytotoxicity was not affected by its knockdown. These findings show that the enhanced efficacy of 5-ALA-PDT in CDDP-resistant cells is primarily driven by increased PpIX accumulation through the upregulation of SLC6A6 and SLC36A1. Thus, 5-ALA-PDT has the potential to be a universal and effective treatment for cancers that develop CDDP resistance.