Premium
Reversal of doxorubicin resistance in breast cancer cells by photochemical internalization
Author(s) -
Lou PeiJen,
Lai PingShan,
Shieh MingJium,
MacRobert Alexander J.,
Berg Kristian,
Bown Stephen G.
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22098
Subject(s) - doxorubicin , endocytic cycle , cytosol , internalization , multiple drug resistance , cancer cell , chemistry , viability assay , cancer research , endocytosis , biophysics , cell , biology , biochemistry , cancer , medicine , chemotherapy , enzyme , antibiotics
Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site‐specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF‐7 and MCF‐7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS 2 a (disulfonated meso‐tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC 50 (drug concentration for 50% reduction in colony formation) was 0.1 μM for MCF‐7 and 1 μM for MCF‐7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC 50 concentration was 0.1 μM for both cell lines. Comparable changes were seen with assay of cell viability using 3‐(4,5‐dimethyltiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF‐7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF‐7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endo‐lysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR. © 2006 Wiley‐Liss, Inc.