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Modulating ALA-PDT efficacy of mutlidrug resistant MCF-7 breast cancer cells using ALA prodrug

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Abstract

Multi-drug resistance of breast cancer is a major obstacle in chemotherapy of cancer treatments. Recently it was suggested that photodynamic therapy (PDT) can overcome drug resistance of tumors. ALA-PDT is based on the administration of 5-aminolevulinic acid (ALA), the natural precursor for the PpIX biosynthesis, which is a potent natural photosensitizer. In the present study we used the AlaAcBu, a multifunctional ALA-prodrug for photodynamic inactivation of drug resistant MCF-7/DOX breast cancer cells. Supplementation of low doses (0.2mM) of AlaAcBu to the cells significantly increased accumulation of PpIX in both MCF-7/WT and MCF-7/DOX cells in comparison to ALA, or ALA + butyric acid (BA). In addition, our results show that MCF-7/DOX cells are capable of producing higher levels of porphyrins than MCF-7/WT cells due to low expression of the enzyme ferrochelatase, which inserts iron into the tetra-pyrrol ring to form the end product heme. Light irradiation of the AlaAcBu treated cells activated efficient photodynamic killing of MCF-7/DOX cells similar to the parent MCF-7/WT cells, depicted by low mitochondrial enzymatic activity, LDH leakage and decreased cell survival following PDT. These results indicate that the pro-drug AlaAcBu is an effective ALA derivative for PDT treatments of multidrug resistant tumors.

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Authors and Affiliations

  1. The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Microscopy Unit, Ramat-Gan, 52900, Israel

    Tamar Feuerstein, Gili Berkovitch-Luria & Zvi Malik

  2. Chemistry Department, Bar-Ilan University, Ramat-Gan, 52900, Israel

    Abraham Nudelman

  3. Laboratory of Pharmacology and Experimental Oncology, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv University, Ramat, Aviv, Israel

    Ada Rephaeli

Authors
  1. Tamar Feuerstein
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  2. Gili Berkovitch-Luria
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  3. Abraham Nudelman
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  4. Ada Rephaeli
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  5. Zvi Malik
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Correspondence to Zvi Malik.

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Feuerstein, T., Berkovitch-Luria, G., Nudelman, A. et al. Modulating ALA-PDT efficacy of mutlidrug resistant MCF-7 breast cancer cells using ALA prodrug. Photochem Photobiol Sci 10, 1926–1933 (2011). https://doi.org/10.1039/c1pp05205e

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  • DOI: https://doi.org/10.1039/c1pp05205e

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