Cross-resistance to cisplatin in cells resistant to photofrin-mediated photodynamic therapy.
This study shows that a Photofrin-induced photodynamic therapy-resistant variant (RIF-8A) of a radiation-induced fibrosarcoma-1 cell line (RIF-1) is cross-resistant to cis-diamminedichloroplatinum(II) (cisplatin). This is the first study to show cross-resistance to cisplatin in photodynamic therapy-resistant variants in vitro. Resistance does not appear to be the result of elevated glutathione levels since neither the resistant variant (RIF-8A) nor the parental line (RIF-1) varied in total glutathione levels. However, cisplatin-DNA adduct levels differed significantly between the two cell types. Immediately following a 1-h exposure to cisplatin (50 microM), RIF-1 cells contained 44.6 +/- 2.0 (SEM) pg platinum/micrograms DNA while RIF-8A cells contained 24.8 +/- 6.3 pg platinum/micrograms DNA. In addition, the resistant variant had decreased plasma and mitochondrial membrane potentials. The plasma and mitochondrial membranes of the resistant variant accumulated 3- and 3.6-fold less rhodamine 123, respectively. The difference in rhodamine 123 accumulation could not be attributed to elevated P-glycoprotein expression because both the parental line and the variant contained similar amounts of P-glycoprotein. In conclusion, alterations in the plasma and/or mitochondrial membrane potentials may provide cells with a survival advantage when challenged with either photodynamic therapy or cisplatin in vitro. This appears to be a novel mechanism of resistance.
Moorehead
R A
RA
Ontario Cancer Treatment and Research Foundation, Hamilton Regional Cancer Centre, Canada.
Armstrong
S G
SG
Wilson
B C
BC
Singh
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000032:analysis; D002470:Cell Survival; D002945:Cisplatin / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D004247:DNA / Q000032:analysis; D018736:DNA Adducts; D004351:Drug Resistance; D005354:Fibrosarcoma / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism* / Q000648:ultrastructure; D005978:Glutathione / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D008564:Membrane Potentials; D008928:Mitochondria / Q000648:ultrastructure*; D009381:Neoplasms, Radiation-Induced / Q000737:chemistry / Q000188:drug therapy / Q000378:metabolism* / Q000648:ultrastructure; D010778:Photochemotherapy; D011166:Porphyrins; D020112:Rhodamine 123; D012235:Rhodamines / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D018736:DNA Adducts; D008562:Membrane Glycoproteins; D011166:Porphyrins; D012235:Rhodamines; C057270:cisplatin-DNA adduct; D020112:Rhodamine 123; D004247:DNA; D005978:Glutathione; D002945:Cisplatin