The multidrug resistance modulator SDZ-PSC 833 potentiates the photodynamic activity of chlorin e6 independently of P-glycoprotein in multidrug resistant human breast adenocarcinoma cells.
Photodynamic therapy has clinical indications in treatment of localized cancers and could be interesting for eradication of local recurrence of chemoresistant tumors. In the present study, the intracellular accumulation and distribution of chlorin e6 was investigated in MCF-7 and in P-glycoprotein overexpressing, doxorubicin resistant MCF-7/DXR cell lines. After 3-h incubation with chlorin e6 (1.7 micro mol.l(-1)), no significant difference in accumulation was observed between MCF-7 and MCF-7/DXR cells. Chlorin e6 cellular efflux did not differ in the two cell lines. The lack of influence of P-glycoprotein was confirmed since SDZ-PSC833 (PSC) had no influence in chlorin e6 accumulation and efflux in MCF-7/DXR cells. The subcellular distribution of chlorin e6 appeared different in MCF-7/DXR than in MCF-7 cells. Double staining colocalization fluorescence microscopy studies were performed to identify the subcellular localization sites for chlorin e6 using organelle probes for endoplasmic reticulum, Golgi apparatus, mitochondria and lysosomes. In MCF-7, chlorin e6 was distributed in all cytoplasmic organelles including endoplasmic reticulum and Golgi. In MCF-7/DXR, a diffuse cytoplasmic distribution was observed excepted for the endoplasmic reticulum and Golgi area in which less chlorin e6 was distributed. In MCF-7/DXR, PSC was found to restore the distribution of chlorin e6 in the endoplasmic reticulum and Golgi area while in MCF-7, no effect on the subcellular distribution of chlorin e6 was observed. Although the photodynamic activity of chlorin e6 (1.7 micro mol.l(-1), 650 nm, 8 mW.cm(-2)) was found to be lower in MCF-7/DXR than in MCF-7 cells, PSC was found to potentiate the photodynamic activity of chlorin e6 to similar extent in both cell lines. These results clearly demonstrate that PSC potentiates the photodynamic activity of Chlorin e6 independently of the expression of P-glycoprotein and further suggest that the photodynamic activity of chlorin e6 could be related to its intracellular distribution in the endoplasmic reticulum and the Golgi.
Merlin
Jean-Louis
JL
Centre Alexis Vautrin, Laboratoire de Recherche en Oncologie, 54511 Vandoeuvre-les-Nancy cedex, France. jl.merlin@nancy.fnclcc.fr
Gautier
Hervé
H
Barberi-Heyob
Muriel
M
Teiten
Marie-Hélène
MH
Guillemin
François
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D002735:Chlorophyllides; D003524:Cyclosporins / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007834:Lasers; D008027:Light; D008856:Microscopy, Fluorescence; D011166:Porphyrins / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D013053:Spectrophotometry; D013347:Subcellular Fractions; D013696:Temperature; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002735:Chlorophyllides; D003524:Cyclosporins; D011166:Porphyrins; D011838:Radiation-Sensitizing Agents; C062985:phytochlorin; C070272:valspodar