An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpesviridae.

Abstract

Cyclin-dependent kinase (CDK) inhibitors have been considered as excellent drug candidates for cancer therapy owing to their potential capacity to restore cell cycle control. The first generation of CDK inhibitors showed modest clinical advantages that could be attributed to off-target effects preventing them from reaching therapeutic concentrations. A phase I dose-escalation study using the second generation multi-CDK inhibitor PHA-793887 was conducted on a total of 19 patients with advanced refractory malignancies in two sites in Europe: the University of Leeds and St. James's Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR). Fifteen patients were treated at IGR. Six among these patients manifested the reactivation of herpes virus replication. In vitro experiments revealed that PHA-793887 severely impaired signaling by toll-like receptors (such as TLR3, TLR4 and TLR9) in dendritic cells (DC), thus suppressing the production of multiple cytokines (type 1 interferon, interleukin-6,-10, -12, and tumor necrosis factorα) by mature DC, as well as the DC-stimulated production of interferon-γ by natural killer cells. Pharmacological inhibition of glycogen synthase-3β (GSK-3β), one of the off-targets of PHA-793887, did not cause such immunological defects. Altogether, these data underscore a hitherto unsuspected immunosuppressive effect of PHA-793887.

• Authors: Mustapha Zoubir, Caroline Flament, Abdelaziz Gdoura, Rastilav Bahleda, Elena Litvinova, Vassili Soumelis, Rosa Conforti, Sophie Viaud, Jean-Charles Soria, Guido Kroemer, Laurence Zitvogel, Nathalie Chaput
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 10 Issue 1 Pg. 118-26 (Jan 01 2011) ISSN: 1551-4005 [Electronic] United States
• PMID: 21200142 (Publication Type: Clinical Trial, Phase I, Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• N-(6,6-dimethyl-5-((1-methylpiperidin-4-yl)carbonyl)-1,4,5,6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-methylbutanamide
• Pyrazoles
• Pyrroles
• Toll-Like Receptors
• Cyclin-Dependent Kinases

Topics

• Adult
• Aged
• Cells, Cultured
• Cyclin-Dependent Kinases (antagonists & inhibitors, metabolism)
• Disease Susceptibility (chemically induced, pathology)
• Female
• Herpesviridae (drug effects, physiology)
• Herpesviridae Infections (chemically induced, pathology)
• Humans
• Immunosuppressive Agents (adverse effects, pharmacology, therapeutic use)
• Leukocytes, Mononuclear (drug effects, metabolism, pathology)
• Male
• Middle Aged
• Neoplasms (drug therapy, enzymology, pathology)
• Pyrazoles (adverse effects, pharmacology, therapeutic use)
• Pyrroles (adverse effects, pharmacology, therapeutic use)
• Signal Transduction (drug effects, immunology)
• Toll-Like Receptors (antagonists & inhibitors, metabolism)