Platinum resistant cancer cells conserve sensitivity to BH3 domains and obatoclax induced mitochondrial apoptosis.
Resistance to cisplatin chemotherapy remains a major hurdle preventing effective treatment of many solid cancers. BAX and BAK are pivotal regulators of the mitochondrial apoptosis pathway, however little is known regarding their regulation in cisplatin resistant cells. Cisplatin induces DNA damage in both sensitive and resistant cells, however the latter exhibits a failure to initiate N-terminal exposure of mitochondrial BAK or mitochondrial SMAC release. Both phenotypes are highly sensitive to mitochondrial permeabilisation induced by exogenous BH3 domain peptides derived from BID, BIM, NOXA (which targets MCL-1 and A1), and there is no significant change in their prosurvival BCL2 protein expression profiles. Obatoclax, a small molecule inhibitor of pro-survival BCL-2 family proteins including MCL-1, decreases cell viability irrespective of platinum resistance status across a panel of cell lines selected for oxaliplatin resistance. In summary, selection for platinum resistance is associated with a block of mitochondrial death signalling upstream of BAX/BAK activation. Conservation of sensitivity to BH3 domain induced apoptosis can be exploited by agents such as obatoclax, which directly target the mitochondria and BCL-2 family.
Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast, Northern Ireland, UK.
Nyree
N
Crawford
Alex D
AD
Chacko
Kienan I
KI
Savage
Francis
F
McCoy
Kelly
K
Redmond
Daniel B
DB
Longley
Dean A
DA
Fennell
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D010984:Platinum / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D007211:Indoles; D010455:Peptides; D011758:Pyrroles; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D010984:Platinum; D000255:Adenosine Triphosphate; D002945:Cisplatin; C520962:obatoclax