Inhibition of nuclear factor kappa B transcription activity drives a synergistic effect of pyrrolidine dithiocarbamate and cisplatin for treatment of renal cell carcinoma.
One of the impeding factors in the effective treatment of metastatic renal cell carcinoma (RCC) is their intrinsic and acquired resistance to chemotherapeutics. Many studies have shown that drug resistance, at least in part, is mediated by the upregulation of anti-apoptotic (Bcl-2) and multidrug resistance molecules (MDR-1 and MRP-1) by the transcription factor nuclear factor kappa B (NF-kappaB). Combining NF-kappaB inhibitors with conventional chemotherapeutics could overcome resistance of cancer cells. In this study, we examined the synergistic effect of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, and cisplatin, on two human metastatic RCC cell lines ACHN and SN12K1. Individual non-toxic concentrations of PDTC and cisplatin, when combined, synergistically induced a significant increase in apoptosis of the two RCC cell lines. In ACHN cells, the groups with nuclear translocation of NF-kappaB showed resistance to apoptosis, but in SN12K1 cells, the groups with NF-kappaB translocation were susceptible to apoptosis. The combination treatment significantly decreased the transcription activity of all NF-kappaB subunits in both cell lines. Anti-apoptotic proteins Bcl-2 and Bcl-(XL) were significantly decreased in the combination therapy group of both cell lines, but MDR-1 was decreased only in the ACHN cells. No changes in MRP-1 were observed in any of the treatment groups. The results demonstrate the potential of PDTC to be an adjunct therapeutic agent. The major mechanism of the synergistic effect appears to be mediated by the inhibition of transcription activity of NF-kappaB rather than its expression, and the resultant decrease in the anti-apoptotic proteins Bcl-2 and Bcl-(XL).
Department of Renal Medicine, Royal Brisbane and Women's Hospital, Herston, QLD, Australia. c.morais@uq.edu.au
Christudas
C
Morais
Glenda
G
Gobe
David W
DW
Johnson
Helen
H
Healy
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D013859:Thiocarbamates / Q000494:pharmacology / Q000627:therapeutic use*; D014158:Transcription, Genetic / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002945:Cisplatin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016328:NF-kappa B; D021122:Protein Subunits; D011759:Pyrrolidines; D013859:Thiocarbamates; D051020:bcl-X Protein; C020972:pyrrolidine dithiocarbamic acid; C421109:multidrug resistance-associated protein 1