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bioRxiv · 10.1101/346031

Time dependent response of daunorubicin on cytotoxicity, cell cycle and DNA repair in acute lymphoblastic leukaemia

Al-Aamri, H. M.·Ku, H.·Irving, H.·Tucci, J.·Meehan-Andrews, T.·Bradley, C.
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Abstract

Daunorubicin is commonly used in the treatment of acute lymphoblastic leukaemia (ALL). Various mechanisms of action for daunorubicin have been proposed and its action is likely to be multi-modal. The aim of this study was to explore the kinetics of double strand break (DSB) formation of three ALL cell lines following exposure to daunorubicin and to investigate the effects of daunorubicin on the cell cycle and the protein kinases involved in specific checkpoints following DNA damage and recovery periods. Three ALL cell lines CCRF-CEM and MOLT-4 derived from T lymphocytes and SUP-B15 derived from B lymphocytes were examined following 4 hours treatment with daunorubicin chemotherapy and varying recovery periods. Daunorubicin induced different degrees of toxicity in all cell lines and consistently generated reactive oxygen species. Daunorubicin was more potent at inducing DSB in MOLT-4 and CCRF-CEM cell lines while SUP-B15 cells showed delays in DSB repair and significantly more resistance to daunorubicin compared to the other cell lines as measured by {gamma}H2AX assay. Daunorubicin also causes cell cycle arrest in all three cell lines at different checkpoints at different times. These effects were not due to mutations in Ataxia-telangiectasia mutated (ATM) as sequencing revealed none in any of the three cell lines. However, p53 was phosphorylated at serine 15 only in CCRF-CEM and MOLT-4 but not in SUP-B15 cells. The lack of active p53 may be correlated to the increase of SOD2 in SUP-B15 cells. The delay in DSB repair and lower sensitivity to daunorubicin seen in the B lymphocyte derived SUP-B15 cells could be due to loss of function of p53 thus causing variations in the DNA repair pathways.

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Al-Aamri, H. M., Ku, H., Irving, H., Tucci, J., Meehan-Andrews, T., Bradley, C.. 2018-06-13. Time dependent response of daunorubicin on cytotoxicity, cell cycle and DNA repair in acute lymphoblastic leukaemia. https://doi.org/10.1101/346031

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