Survivin is not induced by novel taxanes.
Taxanes are a critical component of chemotherapy for breast, prostate, lung and other cancers. Initial or acquired tumor resistance to taxanes is therefore one of the most important issues in oncology. Survivin is a prosurvival gene whose expression is a poor prognostic feature. Survivin is induced acutely upon exposure to taxanes and coordinates resistance to taxane-mediated cell death, although the exact mechanism of taxane-mediated survivin induction is not clear. Here, we describe the synthesis of a series of novel taxanes, with modifications on the 7- or 10-position of the taxane backbone, as well as the side chain. We found that the novel taxanes with modifications at the 10-position have robust tubulin binding and tubulin polymerization activity. Gene expression profiling and quantitative PCR of cells treated with the 10-position conjugates reveals that the effect of treatment with a subset of these novel taxanes lacks a gene expression signature, including survivin induction, which is characteristically induced with paclitaxel treatment. Furthermore, we show that this gene expression signature is not due to differences in G2/M arrest. Cell sensitivity studies suggest that the inability to induce survivin is associated with increased drug cytotoxicity and apoptosis. This work suggests that taxanes that effectively bind tubulin need not invariably induce survivin as a mechanism of drug resistance.
Sharifi
Nima
N
Division of Hematology/Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8852, USA. nima.sharifi@utsouthwestern.edu
Qi
Jun
J
Bane
Susan
S
Sharma
Shubhada
S
Li
Rui
R
Robey
Robert
R
Figg
William D
WD
Farrar
William L
WL
Kingston
David G I
DG
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D015394:Molecular Structure; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D013237:Stereoisomerism; D000077022:Survivin; D043823:Taxoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D043823:Taxoids; D014404:Tubulin; D011065:Poly(ADP-ribose) Polymerases