STX140 and STX641 cause apoptosis via the intrinsic mitochondrial pathway and down-regulate survivin and XIAP expression in ovarian and prostate cancer cells.
Many anticancer drugs target microtubules and induce apoptosis. However, improved microtubule-targeting drugs, such as STX140 and STX641, are being developed. These compounds induce cell cycle arrest and apoptosis in a variety of tumour cells. The mechanisms that induce apoptosis and the key mediators involved are elucidated in this study. Results demonstrate that STX140 and STX641 depolarise mitochondrial bioenergetics and activate caspase 3/7 in A2780, LNCaP and MCF-7 cancer cells. Furthermore, both compounds cause a significant reduction in the expression of survivin and XIAP. This work details the temporal organisation of apoptosis induced by two microtubule disruptors and highlights the role that the down-regulation of survivin and XIAP may play in this process.
Foster
Paul A
PA
Oncology Drug Discovery and Women's Health Group, Faculty of Medicine, Imperial College London, St Mary's Hospital, London, W2 1NY, UK. paul.foster@imperial.ac.uk
Ho
Yaik T
YT
Newman
Simon P
SP
Leese
Mathew P
MP
Potter
Barry V L
BV
Reed
Michael J
MJ
Purohit
Atul
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004963:Estrenes / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000077022:Survivin; D050257:Tubulin Modulators / Q000494:pharmacology
C526437:2-methoxy-3-O-sulfamoyl-17-cyanomethylestra-1,3,5(10)-triene; C526438:2-methoxyestradiol-3,17-O,O-bis(sulfamate); C107489:BIRC5 protein, human; D018797:Cell Cycle Proteins; D004963:Estrenes; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D050257:Tubulin Modulators; D000255:Adenosine Triphosphate; D053148:Caspase 3; D053179:Caspase 7