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

Oncogene. 2015 Jun;34(25):3336-48. doi: 10.1038/onc.2014.266. Epub 2014 Aug 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthraquinones / pharmacology*
  • Anthraquinones / therapeutic use
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • DNA Damage / drug effects
  • DNA Repair / drug effects
  • DNA Replication / drug effects
  • DNA Topoisomerases, Type II / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Leukemia, Lymphoid / drug therapy
  • Leukemia, Lymphoid / genetics
  • Leukemia, Lymphoid / pathology
  • M Phase Cell Cycle Checkpoints / drug effects
  • Mice
  • Topoisomerase Inhibitors / pharmacology*
  • Topoisomerase Inhibitors / therapeutic use
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Alchemix
  • Anthraquinones
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Topoisomerase Inhibitors
  • Tumor Suppressor Protein p53
  • Ataxia Telangiectasia Mutated Proteins
  • DNA Topoisomerases, Type II