Abstract
Photosensitizer protoporphyrin IX (PpIX) fluorescence, intracellular localization and cell response to photodynamic therapy (PDT) were analyzed in MCF10A normal breast epithelial cells and a panel of human breast cancer cells including estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) positive and triple negative breast cancer (TNBC) cells after treatment with PpIX precursor aminolevulinic acid (ALA). Although PpIX fluorescence was heterogeneous in different cells, TNBC cells showed significantly lower PpIX level than MCF10A and ER- or HER2-positive cells. PpIX fluorescence in TNBC cells also had much less mitochondrial localization than other cells. There was an inverse correlation between PpIX fluorescence and cell viability after PDT. Breast cancer cells with the highest PpIX fluorescence were the most sensitive to ALA-PDT and TNBC cells with the lowest PpIX level were resistant to PDT. Treatment of TNBC cells with ABCG2 transporter inhibitor Ko143 significantly increased ALA-PpIX fluorescence, enhanced PpIX mitochondrial accumulation and sensitized cancer cells to ALA-PDT. Ko143 treatment had little effect on PpIX production and ALA-PDT in normal and ER- or HER2-positive cells. These results demonstrate that enhanced ABCG2 activity renders TNBC cell resistance to ALA-PDT and inhibiting ABCG2 transporter is a promising approach for targeting TNBC with ALA-based modality.
Highlights
Upon laser light activation[4]
Its promise in diagnosing primary breast tumor as well as lymph node metastasis has been demonstrated in breast cancer patients, which shows that all primary tumors and metastatic lymph nodes examined in the study exhibit several-fold higher protoporphyrin IX (PpIX) fluorescence than normal tissues after aminolevulinic acid (ALA) administration[13,14]
Our study demonstrated that inhibition of ATP-binding cassette transporter G2 (ABCG2) with Ko143 was able to reverse the resistance of triple-negative breast cancer (TNBC) to ALA-PDT by elevating PpIX level in mitochondria
Summary
Upon laser light activation[4]. Preferential accumulation of photosensitizers in tumor tissues coupled with targeted delivery of activating light to tumor tissues ensures dual selectivity for tumor destruction. Its promise in diagnosing primary breast tumor as well as lymph node metastasis has been demonstrated in breast cancer patients, which shows that all primary tumors and metastatic lymph nodes examined in the study exhibit several-fold higher PpIX fluorescence than normal tissues after ALA administration[13,14]. It is not yet known whether ER-positive, HER2-positive and TNBC cells have similar response to ALA-based imaging and therapy. Our study demonstrated that inhibition of ATP-binding cassette transporter G2 (ABCG2) with Ko143 was able to reverse the resistance of TNBC to ALA-PDT by elevating PpIX level in mitochondria
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