Chandratre Sharayu, Olsen Jordyn, Chen Bin
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, Saint Joseph's University, Philadelphia, Pennsylvania, USA.
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Photochem Photobiol. 2025 Feb 3. doi: 10.1111/php.14077.
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.
我们报告了获得性肿瘤细胞对5-氨基酮戊酸（ALA）介导的光动力疗法（PDT）联合ABCG2抑制产生耐药性的情况。ALA-PDT联合ABCG2工具抑制剂Ko143或重新利用的临床相关ABCG2抑制剂拉帕替尼在根除H4人胶质瘤细胞方面非常有效，治疗后细胞存活率极低。然而，在进行七轮光剂量递增的重复治疗后，产生的肿瘤细胞对联合疗法产生了耐药性。耐药亚系和亲本细胞系显示出相似的ABCG2活性和蛋白水平，表明耐药性并非由ABCG2引起。它们对PpIX-PDT和mTOR抑制剂AZD2014也表现出相似的反应，这表明PDT敏感性和mTOR通路的改变对耐药表型的发展贡献不大。通过测定细胞内和细胞外的PpIX水平、血红素生物合成酶的活性和蛋白水平，我们发现耐药亚系中胆色素原脱氨酶（PBGD）的活性和蛋白水平显著降低，通过大幅减少PpIX生物合成导致对PDT产生耐药性。一种新的对ALA-PDT联合ABCG2抑制的获得性耐药机制已被揭示。
