Mitoxantrone in combination with an inhibitor of DNA-dependent protein kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia.

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BlankMitoxantrone in combination with an inhibitor of DNA-dependent protein

kinase: a potential therapy for high risk B-cell chronic lymphocytic leukaemia.

SL Elliott, C Crawford, E Mulligan, G Summerfield, P Newton, J Wallis, T

Mainou-Fowler, P , C Bedwell, BW Durkacz, and E Willmore

Br J Haematol, November 18, 2010; .

The Newcastle Cancer Centre at the Northern Institute for Cancer Research,

Newcastle University, Newcastle upon Tyne Queen Hospital, Gateshead

Sunderland Royal Hospital, Sunderland Freeman Hospital, Newcastle upon Tyne St

University Hospital, Leeds Northern Genetics Service, Newcastle upon Tyne

NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK.

Defects in the DNA damage response pathway [e.g. del(17p)] are associated with

drug-resistant B-cell chronic lymphocytic leukaemia (CLL). We previously

demonstrated that over-expression of DNA-dependent protein kinase (DNA-PK)

correlates with chemo-resistance and that inhibition of DNA-PK sensitizes CLL

cells to chemotherapeutics. Here, we investigated expression of DNA-PK and other

proteins that impact on drug resistance, and evaluated the effects of a DNA-PK

inhibitor (NU7441) on mitoxantrone-induced cytotoxicity in CLL cells. NU7441

sensitized cells from 42/49 CLL samples to mitoxantrone, with sensitization

ranging from 2- to 200-fold Co-culture of CLL cells in conditioned stromal

medium increased chemoresistance but did not reduce sensitization by NU7441.

Mitoxantrone treatment induced ?H2AX foci and NU7441 increased their longevity

(24?h). NU7441 prevented mitoxantrone-induced autophosphorylation of the DNA-PK

catalytic subunit (DNA-PKcs) at Ser 2056, confirming that DNA-PK participates in

repair of mitoxantrone-induced DNA damage. del(17p) cases were more resistant to

mitoxantrone than del(13q) cases, but were resensitized (7-16?fold) by

co-incubation with NU7441. Expression of DNA-PKcs, Ku80, P-glycoprotein and

topoisomerase II? were significantly higher in del(17p) cases. PRKDC mRNA levels

correlated with DNA-PKcs protein expression, which predicted shorter survival.

These data confirm the potential of DNA-PK as a therapeutic target in poor

prognosis CLL.

PMID: 21083655