Survivin Is Not Induced by Novel Taxanes

• Published in: Molecular pharmaceutics 2010-12, Vol.7 (6), p.2216-2223
• Main Authors: Sharifi, Nima, Qi, Jun, Bane, Susan, Sharma, Shubhada, Li, Rui, Robey, Robert, Figg, William D, Farrar, William L, Kingston, David G. I
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Binding, Competitive - drug effects; Cell Cycle - drug effects; Cell Proliferation - drug effects; Drug Screening Assays, Antitumor; Humans; Inhibitor of Apoptosis Proteins; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Molecular Structure; Poly(ADP-ribose) Polymerases - metabolism; Polymerase Chain Reaction; Stereoisomerism; Taxoids - chemical synthesis; Taxoids - chemistry; Taxoids - pharmacology; Tubulin - chemistry; Tubulin - metabolism; Tumor Cells, Cultured
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp100211k

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.