Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells.
Chemotherapy and radiotherapy can cause permanent damage to the genomes of surviving cells, provoking severe side effects such as second malignancies in some cancer survivors. Drugs that mimic the activity of death ligands, or antagonise pro-survival proteins of the Bcl-2 or IAP families have yielded encouraging results in animal experiments and early phase clinical trials. Because these agents directly engage apoptosis pathways, rather than damaging DNA to indirectly provoke tumour cell death, we reasoned that they may offer another important advantage over conventional therapies: minimisation or elimination of side effects such as second cancers that result from mutation of surviving normal cells. Disappointingly, however, we previously found that concentrations of death receptor agonists like TRAIL that would be present in vivo in clinical settings provoked DNA damage in surviving cells. In this study, we used cell line model systems to investigate the mutagenic capacity of drugs from two other classes of direct apoptosis-inducing agents: the BH3-mimetic ABT-737 and the IAP antagonists LCL161 and AT-406. Encouragingly, our data suggest that IAP antagonists possess negligible genotoxic activity. Doses of ABT-737 that were required to damage DNA stimulated Bax/Bak-independent signalling and exceeded concentrations detected in the plasma of animals treated with this drug. These findings provide hope that cancer patients treated by BH3-mimetics or IAP antagonists may avoid mutation-related illnesses that afflict some cancer survivors treated with conventional DNA-damaging anti-cancer therapies.
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia.
Tanmay M
TM
Shekhar
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia; Department of Anatomy & Neuroscience, The University of Melbourne, Parkville 3010, Australia.
Maja M
MM
Green
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia.
David M
DM
Rayner
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia.
Mark A
MA
Miles
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia.
Suzanne M
SM
Cutts
Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora 3083, Australia. Electronic address: c.hawkins@latrobe.edu.au.
Christine J
CJ
Hawkins
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001392:Azocines / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
C501332:ABT-737; D000970:Antineoplastic Agents; D001392:Azocines; C494827:Bax protein, mouse; D001559:Benzhydryl Compounds; D001713:Biphenyl Compounds; D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D009153:Mutagens; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D013844:Thiazoles; D051028:bcl-2-Associated X Protein
Bcl-2; DNA damage; Genotoxic; IAP; Late effects; Second malignant neoplasms