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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo
Lihua Yang1, Erin Jackson, B Mark Woerner
1Department of Pediatrics, and Neurology and Molecular Imaging Center, Mallinckrodt Institute of Radiology, Washington University School of Medicine and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
Abstract:
The chemokine CXCL12 and its cognate receptor CXCR4 regulate malignant brain tumor growth and are potential chemotherapeutic targets. However, the molecular basis for CXCL12-induced tumor growth remains unclear, and the optimal approach to inhibiting CXCR4 function in cancer is unknown. To develop such a therapeutic approach, we investigated the signaling pathways critical for CXCL12 function in normal and malignant cells. We discovered that CXCL12-dependent tumor growth is dependent upon sustained inhibition of cyclic AMP (cAMP) production, and that the antitumor activity of the specific CXCR4 antagonist AMD 3465 is associated with blocking cAMP suppression. Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465. These data indicate that the clinical evaluation of phosphodiesterase inhibitors in the treatment of patients with brain tumors is warranted.
Insights
CXCL12/CXCR4 signaling drives malignant brain tumor growth by suppressing cyclic AMP (cAMP). Inhibiting this pathway with phosphodiesterase inhibitors shows therapeutic promise for brain tumors.
Area of Science:
- Oncology
- Molecular Biology
- Neuroscience
Background:
- The CXCL12/CXCR4 axis is implicated in malignant brain tumor progression.
- Understanding the molecular mechanisms of CXCL12-induced tumor growth is crucial for developing targeted therapies.
- Optimal strategies for inhibiting CXCR4 in cancer remain to be defined.
Purpose of the Study:
- To elucidate the signaling pathways mediating CXCL12 function in normal and malignant cells.
- To identify therapeutic targets for inhibiting CXCR4 in malignant brain tumors.
Main Methods:
- Investigated CXCL12 signaling pathways in normal and malignant cells.
- Assessed the role of cyclic AMP (cAMP) in CXCL12-dependent tumor growth.
- Evaluated the efficacy of a CXCR4 antagonist (AMD 3465) and a phosphodiesterase inhibitor (Rolipram).
- Utilized in vitro cell culture and intracranial xenograft models.
Main Results:
- CXCL12-dependent tumor growth requires sustained inhibition of cAMP production.
- The antitumor activity of AMD 3465 correlates with its ability to block cAMP suppression.
- Pharmacologic elevation of cAMP using Rolipram suppressed tumor cell growth in vitro.
- Rolipram demonstrated comparable efficacy to AMD 3465 in inhibiting intracranial tumor growth in vivo.
Conclusions:
- Sustained cAMP inhibition is a critical mechanism in CXCL12-driven malignant brain tumor growth.
- Phosphodiesterase inhibitors represent a viable therapeutic strategy for brain tumors.
- Clinical evaluation of phosphodiesterase inhibitors for brain tumor treatment is warranted.
