The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

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The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53. / Thomas, A.; Perry, T.; Berhane, S.; Oldreive, C.; Zlatanou, A.; Williams, L. R.; Weston, V. J.; Stankovic, T.; Kearns, P.; Pors, K.; Grand, R. J.; Stewart, G. S.

In: Oncogene, Vol. 34, No. 25, 06.2015, p. 3336-3348.

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@article{b701f2fe33564943b57ba3a2c0c75d60,
title = "The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53",
abstract = "Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes.",
author = "A. Thomas and T. Perry and S. Berhane and C. Oldreive and A. Zlatanou and Williams, {L. R.} and Weston, {V. J.} and T. Stankovic and P. Kearns and K. Pors and Grand, {R. J.} and Stewart, {G. S.}",
year = "2015",
month = jun,
doi = "10.1038/onc.2014.266",
language = "English",
volume = "34",
pages = "3336--3348",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "25",

}

RIS

TY - JOUR

T1 - The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53

AU - Thomas, A.

AU - Perry, T.

AU - Berhane, S.

AU - Oldreive, C.

AU - Zlatanou, A.

AU - Williams, L. R.

AU - Weston, V. J.

AU - Stankovic, T.

AU - Kearns, P.

AU - Pors, K.

AU - Grand, R. J.

AU - Stewart, G. S.

PY - 2015/6

Y1 - 2015/6

N2 - Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes.

AB - Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes.

UR - http://www.scopus.com/inward/record.url?scp=84931564622&partnerID=8YFLogxK

U2 - 10.1038/onc.2014.266

DO - 10.1038/onc.2014.266

M3 - Article

C2 - 25132271

AN - SCOPUS:84931564622

VL - 34

SP - 3336

EP - 3348

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 25

ER -