ABCG2 transporter inhibitor restores the sensitivity of triple negative breast cancer cells to aminolevulinic acid-mediated photodynamic therapy.
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.
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania, USA.
Pratheeba
P
Palasuberniam
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania, USA.
Xue
X
Yang
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania, USA.
Daniel
D
Kraus
Department of Biological Sciences, Misher College of Arts &Sciences, University of the Sciences, Philadelphia, Pennsylvania, USA.
Patrick
P
Jones
Department of Biological Sciences, Misher College of Arts &Sciences, University of the Sciences, Philadelphia, Pennsylvania, USA.
Kenneth A
KA
Myers
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania, USA.
Bin
B
Chen
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004357:Drug Synergism; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D008027:Light; D008314:Malonates / Q000008:administration & dosage*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000008:administration & dosage; D011836:Radiation Tolerance / Q000528:radiation effects; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology
C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D008314:Malonates; D009363:Neoplasm Proteins; D017319:Photosensitizing Agents; C019249:aminomalonic acid; D000241:Adenosine