Cancer cells having a wild type p53 were sensitive while those with abnormal p53 (mutated or null) were resistant to bortezomib treatment. Consistent with

these findings, previous studies found that wild type p53 transcriptionally inhibits Vismodegib solubility dmso survivin expression in various cancer cell types [27–29] and bortezomib can stabilize wild type p53 in prostate cancer cells [40]. Here, we would like to point out that the bortezomib concentration used affects the results, suggesting the dose used in the clinic should be carefully considered. When high dose may kill cancer cells better in a short term, high dose will increase the possibility to generate bortezomib resistance, suggesting that in addition to p53 status-associated survivin expression,

other factors, such as other protein members in the IAP and Bcl-2 families may also play important roles in bortezomib resistance. Nevertheless, we have confirmed a role for survivin in bortezomib resistance by direct silencing of survivin expression using survivin-specific siRNA/shRNA. This finding is significant because our recent studies indicated that survivin may be a superior LY294002 cancer stem cell marker and possibly plays critical role in cancer stem cell expansion [41]. In this regard, cancer cells appear to have a higher percentage of subpopulation cells that are tumorigenic (cancer initiating/cancer

stem cells) in xenograft mouse Glutathione peroxidase models [42]. Therefore, consideration of both survivin expression and p53 status as interconnecting biomarkers and targets in cancer cells may not only be useful for predicting the outcome of bortezomib treatment, but may also provide pivotal criteria for rational drug combination. For example, bortezomib likely induces survivin expression in cancer cells with mutated or null p53 (this study), and it is known that paclitaxel rapidly induces survivin expression [43]. Thus, combination of bortezomib and paclitaxel likely obtained no good results in many cancer types with such as the mutated p53 background. Accordingly, a recent Phase II study in patients with metastatic esophageal, gastric, and gastroesophageal cancer showed poor results in the drug combination [44]. However, it is also possible that the poor results derived from such a drug combination involve other mechanisms of drug resistance in these tumors that are notoriously difficult to treat with chemotherapy. An important question that needs be answered for better application of the findings is the mechanism underlying bortezomib-mediated induction of survivin expression in mutated or null p53 cancer cells, while it showed downregulation of or minimal effect on survivin expression in wild type p53 cancer cells.