In vitro and in vivo downregulation of MRP1 by antisense oligonucleotides: a potential role in neuroblastoma therapy.
The expression of MRP1 (multidrug resistance protein-1) is associated with chemoresistance and poor prognosis in neuroblastoma. MRP1 antisense oligonucleotides were used in an in vivo mouse-human xenograft model of neuroblastoma to downregulate MRP1. The MRP1 ASO reduced protein levels of MRP1 to an average of 40% of the nil treated controls (p = 0.007). There was significant chemosensitisation to single-agent chemotherapy, VP16 (etoposide), at 1 microg/mL (p = 0.035) and 10 microg/mL (p = 0.02) in comparison to tumours not receiving oligonucleotides. In contrast, MDR1-ASO produced significant chemosensitisation only at 10 microg/mL of VP16 (p = 0.029). No significant chemosensitisation was seen following nonsense oligonucleotides. The downregulation of MRP1 was also associated with an increase in tumour cell death (79% increase in apoptosis index p = 0.0313) and a reduction in cell turnover (42% reduction in mitotic index p = 0.0313), which was not seen with any other oligonucleotide. This new and novel perspective of MRP1 function, which is an apparent involvement in apoptosis and cell cycle progression in neuroblasts, presents a fresh avenue for investigation of the biologic consequences of MRP1 expression that occurs in many tumour cell types. Our work is the first to concurrently explore the effects of downregulation of MRP1 and MDR1 by antisense oligonucleotides in a neuroblastoma xenograft model. It provides rationale for the investigation of therapy adjuvants such as antisense oligonucleotides in the treatment of this malignancy.
Kuss
Bryone J
BJ
Institute of Child Health, University College London, London, United Kingdom. bryone.kuss@flinders.edu.au
Corbo
Margherita
M
Lau
Wen Min
WM
Fennell
Dean A
DA
Dean
Nicholas M
NM
Cotter
Finbarr E
FE
D000818:Animals; D017209:Apoptosis; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016376:Oligonucleotides, Antisense; C421109:multidrug resistance-associated protein 1