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1. Oncogene. 2012 Apr 23. doi: 10.1038/onc.2012.133. [Epub ahead of print]

Multidrug-resistant cells overexpressing P-glycoprotein are susceptible to DNA
crosslinking agents due to attenuated Src/nuclear EGFR cascade-activated DNA
repair activity.

Lee PC, Lee HJ, Kakadiya R, Sanjiv K, Su TL, Lee TC.

1] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [2] School
of Medicine, Institute of Pharmacology, National Yang-Ming University, Taipei,
Taiwan.

We synthesized several novel bifunctional alkylating derivatives of
3a-aza-cyclopenta[a]indene (BO-1012, BO-1005, BO-1099 and BO-1101) that are
potent DNA interstrand crosslinking agents. In in vitro cytotoxicity assay, these
compounds were more cytotoxic to multidrug-resistant (MDR) cells, such as
KBvin10, KBtax50 and CEM/VBL, than their parental cells. Using a xenograft model,
BO-1012, at a dose of 5 mg/kg, partially suppressed the growth of parental KB
cells but completely suppressed the growth of KBvin10 cells in nude mice. In
exploring the possible mechanism, we found that DNA double-strand break (DSB)
repair activity in MDR cells, KBvin10 and CEM/VBL, was significantly reduced
compared with their parental cells, KB and CEM. Reduced DSB repair activity in
KBvin10 cells was likely due to a defect in nuclear translocation of
DNA-dependent protein kinase (DNA-PK), a component of the non-homologous
end-joining repair machinery. Furthermore, BO-1012-induced DNA-PK translocation
from the cytosol into the nucleus in KB cells is associated with the activation
of the Src/nuclear epidermal growth factor receptor (EGFR) cascade, which is
defective in MDR cells. As knockdown of P-glycoprotein (P-gp) by siRNA
reactivated the Src/nuclear EGFR cascade, DNA-PK translocation and DNA repair
activity in MDR cells, overexpression of P-gp attenuates the activity of DNA DSB
repair through suppression of Src/nuclear EGFR cascade. Therefore, DNA
interstrand crosslinking agents may have potential therapeutic use against
P-gp-overexpressing MDR cells.Oncogene advance online publication, 23 April 2012;
doi:10.1038/onc.2012.133.

PMID: 22525278 [PubMed - as supplied by publisher]