A novel acquired resistance mechanism to 5-aminolevulinic acid-mediated photodynamic therapy with ABCG2 inhibition.

Abstract

We report the occurrence of acquired tumor cell resistance to 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (PDT) in combination with ABCG2 inhibition. ALA-PDT in combination with either an ABCG2 tool inhibitor Ko143 or a repurposed clinically-relevant ABCG2 inhibitor lapatinib was highly effective in eradicating the H4 human glioma cells, resulting in minimal cell survival after treatment. However, after seven rounds of repeated treatments with light dose escalation, the resultant tumor cells became resistant to the combination therapy. The resistant sublines and the parental cell line showed similar ABCG2 activities and protein levels, indicating that it was not ABCG2 that caused the resistance. They also exhibited similar responses to PpIX-PDT and mTOR inhibitor AZD2014, suggesting that alterations in PDT sensitivity and mTOR pathway had little contribution to the development of resistance phenotype. By determining the intracellular and extracellular PpIX levels, the activities and protein levels of heme biosynthesis enzymes, we found that porphobilinogen deaminase (PBGD) activity and protein level were significantly reduced in the resistant sublines, causing resistance to PDT by substantially reducing PpIX biosynthesis. A novel acquired resistance mechanism to ALA-PDT with ABCG2 inhibition has been uncovered.