Treating brain tumors with PDE4 inhibitors

doi:10.1016/j.tips.2011.02.015

Trends in Pharmacological Sciences

Volume 32, Issue 6, June 2011, Pages 337-344

https://doi.org/10.1016/j.tips.2011.02.015 Get rights and content

Speculation regarding dysregulation of cAMP metabolism in oncogenesis has existed since the discovery of cAMP more than 50 years ago. Recent data confirm the relevance of disordered cAMP metabolism to the genesis of multiple cancers and suggest that the mechanism might involve altered expression and activity of phosphodiesterases (PDEs). These discoveries coincide with the rapid development and clinical evaluation of PDE inhibitors for non-cancer indications. Thus, the time is ripe to evaluate PDE inhibitors as cancer chemotherapeutics. Here we highlight recent evidence that abnormal regulation of cAMP levels might be a determinant of brain tumorigenesis and that altered PDE expression is one the mechanisms of its dysregulation. Recent preclinical and clinical experience with inhibitors of PDE4 indicates that this might be a promising approach to brain tumor therapy.

Introduction

The 1971 Nobel Prize in Physiology or Medicine was awarded to Earl Sutherland for the discovery of the first second messenger, 3′,5′-cyclic adenosine monophosphate (cAMP) [1]. In his Nobel address, Sutherland noted that ‘defective cyclic AMP formation may be involved in the growth of tumors.’ In our opinion, Sutherland's prediction is proving correct, and therapeutic manipulation of cyclic nucleotide levels might be applicable to multiple cancer types [2]. In this article, we focus on data that suggest that low levels of cAMP play a crucial role in brain tumorigenesis. Furthermore, elevation of cAMP by blocking its degradation with PDE4 inhibitors might have significant clinical value in the treatment of brain tumors.

Section snippets

cAMP as a determinant of brain tumorigenesis

The first specific connection between cAMP levels and brain cancers was reported in 1977 by Furman and Schulman [3]. They found an inverse relationship between cAMP levels and the degree of malignancy in several types of brain tumors. High cAMP levels were associated with more benign tumors, whereas lower levels were correlated with greater malignancy. These findings are consistent with subsequent studies indicating that high concentrations of cAMP inhibit the growth of many cell types,

Mechanisms of cAMP dysregulation in brain tumors

Overall, the above data indicate that altered cAMP levels might be critical in the genesis and progression of brain tumors. cAMP is synthesized by adenylyl cyclases (ACs) and degraded by a single superfamily of hydrolases, the PDEs. The mechanisms underlying altered cAMP signaling in brain tumors are not completely understood, but could include changes in AC or PDE expression and activity.

Growth regulatory targets for cAMP signaling

cAMP can inhibit the growth of normal and neoplastic neural cell types through multiple mechanisms, including regulation of the cell cycle, apoptosis and differentiation. Several studies have linked the anti-proliferative effects of cAMP in astrocytes and astrocytoma cells to G1 cell-cycle arrest. cAMP-dependent cell-cycle arrest involves reduced expression of cyclins A and D1, and increased expression of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 6, 35, 36.

Furthermore, gene

Clinical applications

The growth inhibitory effects of cAMP prompted early speculation about the potential anti-cancer effects of cAMP and cAMP-elevating drugs. For example, cAMP analogs such as 8-chloro-cAMP and dibutyryl-cAMP have significant growth-inhibitory effects but are associated with dose-limiting toxicity [44]. The focus of therapeutic cAMP elevation has been on modulating cAMP levels in other fashions. Thus, it is reasonable to consider modulation of GPCR functions and/or AC and PDE activity.

Targeting of

Concluding remarks

The time is ripe for the application of cAMP-elevating drugs to cancer therapeutics. PDEs have been implicated in carcinogenesis and tumor progression for a variety of tumor types, including prostate cancer [49], brain tumors 5, 11, 19, hematological malignancies 50, 51, colon cancer [52] and melanoma [53], and in the enhancement of drug delivery [54]. Various PDE inhibitors have been or are being actively clinically evaluated (Table 3).

However, several important issues must be addressed before

Acknowledgements

This work was supported by NCI/NIH RO1CA118389 (JBR). The authors have no conflicts of interest to disclose.

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Trends in Pharmacological Sciences

OpinionTreating brain tumors with PDE4 inhibitors

Introduction

Section snippets

cAMP as a determinant of brain tumorigenesis

Mechanisms of cAMP dysregulation in brain tumors

Growth regulatory targets for cAMP signaling

Clinical applications

Concluding remarks

Acknowledgements

Dev. Biol.

BMC Cancer

Prog. Brain Res.

J. Neuroimmunol.

Am. J. Pathol.

Cancer Lett.

Trends Biochem. Sci.

Drug Discov Today

Biochem. Biophys. Res. Commun.

Cancer Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Prog. Med. Chem.

Brain Res.

Blood

J. Biol. Chem.

J. Mol. Biol.

[Nobel prize in physiology or medicine 1971: the action of hormones outlined]

Lakartidningen

Targeting cancer with phosphodiesterase inhibitors

Expert Opin. Investig. Drugs

Cyclic AMP and adenyl cyclase in brain tumors

J. Neurosurg.

Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic glioma growth in neurofibromatosis type 1

Cancer Res.

Blocking CXCR4-Mediated Cyclic AMP Suppression Inhibits Brain Tumor Growth In vivo

Cancer Res.

The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells

Cancer Biol. Ther.

BDNF and PDE4, but not the GRPR, regulate viability of human medulloblastoma cells

J. Mol. Neurosci.

Neurofibromatosis type 1 – a model for nervous system tumour formation?

Nat. Rev. Cancer

Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1

Cancer Res.

cAMP phosphodiesterase-4A1 (PDE4A1) has provided the paradigm for the intracellular targeting of phosphodiesterases, a process that underpins compartmentalized cAMP signalling

Biochem. Soc. Trans.

Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs

Curr. Pharm. Des.

PET measurement of the in vivo affinity of 11C-(R)-rolipram and the density of its target, phosphodiesterase-4, in the brains of conscious and anesthetized rats

J. Nucl. Med.

Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs

Curr. Pharm. Des.

The role of phosphodiesterases in schizophrenia: therapeutic implications

CNS Drugs

Expression of phosphodiesterase 4 is altered in the brains of subjects with autism

Neuroreport

Targeted inhibition of cyclic AMP phosphodiesterase-4 promotes brain tumor regression

Clin. Cancer Res.

Opinion
Treating brain tumors with PDE4 inhibitors

PET measurement of the in vivo affinity of ¹¹C-(R)-rolipram and the density of its target, phosphodiesterase-4, in the brains of conscious and anesthetized rats