Small-molecule multidrug resistance-associated protein 1 inhibitor reversan increases the therapeutic index of chemotherapy in mouse models of neuroblastoma.
The multidrug resistance-associated protein 1 (MRP1) has been closely linked to poor treatment response in several cancers, most notably neuroblastoma. Homozygous deletion of the MRP1 gene in primary murine neuroblastoma tumors resulted in increased sensitivity to MRP1 substrate drugs (vincristine, etoposide, and doxorubicin) compared with tumors containing both copies of wild-type MRP1, indicating that MRP1 plays a significant role in the drug resistance in this tumor type and defining this multidrug transporter as a target for pharmacologic suppression. A cell-based readout system was created to functionally determine intracellular accumulation of MRP1 substrates using a p53-responsive reporter as an indicator of drug-induced DNA damage. Screening of small-molecule libraries in this readout system revealed pyrazolopyrimidines as a prominent structural class of potent MRP1 inhibitors. Reversan, the lead compound of this class, increased the efficacy of both vincristine and etoposide in murine models of neuroblastoma (syngeneic and human xenografts). As opposed to the majority of inhibitors of multidrug transporters, Reversan was not toxic by itself nor did it increase the toxicity of chemotherapeutic drug exposure in mice. Therefore, Reversan represents a new class of nontoxic MRP1 inhibitor, which may be clinically useful for the treatment of neuroblastoma and other MRP1-overexpressing drug-refractory tumors by increasing their sensitivity to conventional chemotherapy.
Burkhart
Catherine A
CA
Cleveland BioLabs, Inc, Buffalo, New York, USA.
Watt
Fujiko
F
Murray
Jayne
J
Pajic
Marina
M
Prokvolit
Anatoly
A
Xue
Chengyuan
C
Flemming
Claudia
C
Smith
Janice
J
Purmal
Andrei
A
Isachenko
Nadezhda
N
Komarov
Pavel G
PG
Gurova
Katerina V
KV
Sartorelli
Alan C
AC
Marshall
Glenn M
GM
Norris
Murray D
MD
Gudkov
Andrei V
AV
Haber
Michelle
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D004285:Dogs; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D054852:Small Molecule Libraries / Q000032:analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D054852:Small Molecule Libraries; C543413:reversan; C421109:multidrug resistance-associated protein 1