Roscovitine Is an Effective Inducer of Apoptosis of Ewing's Sarcoma Family Tumor CellsIn vitroandIn vivo

Abstract

The Ewing's sarcoma family of tumors (ESFT) comprises several well-characterized malignant neoplasms with particularly aggressive behavior. Despite recent progress in the use of multimodal therapeutic approaches and aggressive local control measures, a substantial proportion of patients die because of disease progression. Furthermore, this outcome has not changed significantly over the last 15 to 20 years. Consequently, new, more effective therapeutic options are sorely needed for the treatment of ESFT. Because ESFT cells overexpress several cyclin-dependent kinases (CDK), we explored the efficacy against ESFT of roscovitine, a CDK inhibitor shown to be surprisingly safe for humans in clinical trials of their anticancer activity. Results showed that ESFT cell lines are uniformly sensitive to roscovitine. In addition to exerting comparatively minor cell cycle effects, roscovitine treatment concomitantly caused the up-regulation of the expression of the proapoptotic protein BAX and the downregulation of both survivin and XIAP, thus resulting in caspase-dependent apoptosis. Furthermore, in vivo experiments showed that s.c. growth of ESFT xenografts was also significantly slowed by i.p. injection of roscovitine. These results strongly suggest that roscovitine may be an effective therapeutic agent against ESFT and recommend its evaluation against ESFT in clinical trials and its inclusion in future treatment protocols. (Cancer Res 2005; 65(20): 9320-27)

The cyclin-dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine

“…[28][29][30] CDKs have an essential role in cell proliferation and their potential as molecular targets for anti-cancer therapies has becoming increasingly recognised. 31 As the development of the pan CDK inhibitor flavopiridol more specific CDK inhibitors have been developed [32][33][34] with encouraging results. In this study, we present our findings on the CDK inhibitor SNS-032 in primary AML cells both alone and in combination with Ara-C. SNS-032 resulted in in vitro cell killing, at a sub-micromolar level, in samples derived from 87 newly diagnosed AML patients.…”

Increased Survivin Expression Confers Chemoresistance to Tumor-Associated Endothelial Cells

“…We used both a genetic and pharmacological approach to reduce survivin in TuBECs. However, because lentiviral agents are not currently used in the clinic, we tested a pharmacological agent, roscovitine, a Cdk1 inhibitor 24 that prevents the phosphorylation of survivin and thereby decreases its stability. Co-treatment with roscovitine enhanced the response of TuBECs to VP-16, paclitaxel, and thapsigargin.…”

“…Therefore, we examined the effects of pharmacological inhibitors of survivin. The drug roscovitine, a Cdk1 inhibitor that is used in vitro and in vivo, was shown to reduce survivin levels 24 by decreasing the stability of the survivin protein in tumor cell lines. To determine whether this agent could alter survivin expression in TuBECs, the cells were treated with roscovitine for 24 hours and analyzed for survivin protein using Western blot analysis ( Figure 7A).…”

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

“…Interestingly, a study dosing mice bearing an Ewing's Sarcoma cell line A4573 with only 50mg/kg of roscovitine once per day has shown the most striking single-agent antitumour activity, inhibiting tumour growth by 85%, when compared to untreated animals [129]. Our results and data form other laboratories on anti-tumour activity of CYC202 in vivo are summarised in Table 3.…”

“…The lack of activity of roscovitine on hematopoietic progenitors in vivo was not expected, since an inhibitory effect in vitro was observed, along with the reported activity on different xenografts in vivo [100,124,129,140]. Therefore, we decided to study the distribution and PK of roscovitine in Balb/c mice.…”