The Type IV Phosphodiesterase Inhibitor Rolipram Induces Expression Inhibitors p21Cip1 and p27Kip1, Resulting in Growth Inhibition, Increased Differentiation, and Subsequent Apoptosis of Malignant A-172 Glioma Cells

Abstract

Upregulation of the cAMP/protein kinase A (PKA) pathway has been shown to result in decreased proliferation, increased differentiation, and subsequent apoptosis of malignant glioma cells. Conventional cAMP analogs, however, are difficult to use in a clinical setting. Therefore, we investigated the effects of rolipram, a drug that has undergone clinical trials as an antidepressant and has also been proposed as a treatment for multiple sclerosis. Rolipram acts as a specific inhibitor of type IV phosphodiesterase (PDE4), leading to increased intracellular levels of cAMP. We report that the inhibition of PDE4 by rolipram results in the activation of the cAMP/PKA pathway, with potent stimulation of a reporter gene containing a cAMP-responsive element in its promoter region. Further, treatment of the human glioma cell line A-172 with rolipram results in increased expression of the cell cycle inhibitors p21(Cip1) and p27(KiP1), and decreased activity of cdk2, a cyclin-dependent kinase essential for cell cycle progression. As a result, the proliferation of A-172 cells is inhibited, with induction of a Gl block. Eventually, rolipram-treated A-172 cells undergo differentiation, which is followed by apoptotic cell death. As we observe this effect with other glioma cell cultures as well, our results suggest that rolipram could prove useful as a novel differentiating agent with both cytostatic and cytotoxic potential in the treatment of malignant gliomas.

Developmental Exposure to Estradiol and Bisphenol A Increases Susceptibility to Prostate Carcinogenesis and Epigenetically Regulates Phosphodiesterase Type 4 Variant 4

“…Sustained expression of PDE4D4 by hypomethylation could thus result in decreased intracellular cAMP in specific subcellular locations, creating a potential for aberrant cell signaling and potentially neoplastic transformation. In this regard, recent studies have shown a tight association between PDE4 expression and cancer cell proliferation, including glioma cells (47), osteosarcomas (48), and chronic lymphocytic leukemia (49). Importantly, PDE4 is currently being pursued as a possible chemotherapeutic target (50).…”

Developmental estrogen exposures predispose to prostate carcinogenesis with aging☆

“…Thus persistent activation of cAMP pathways may contribute to neoplastic transformation. In this regard, recent studies have shown a tight association between PDE4 expression and cancer cell proliferation, including glioma cells (87), osteosacromas (88) and chronic lymphocytic leukemia (89). Furthermore, PDE4 is currently being pursued as a possible chemotherapeutic target (90).…”

Chemoresistant KM12C Colon Cancer Cells Are Addicted to Low Cyclic AMP Levels in a Phosphodiesterase 4–Regulated Compartment via Effects on Phosphoinositide 3-Kinase

“…For example, the archetypal PDE3-selective inhibitor cilostazol (12) and the archetypal PDE4-selective inhibitor rolipram (7) both suppress colon cancer cell motility (13), whereas inhibition PDE4 by rolipram can negatively affect chronic lymphocytic leukemia (14). Interestingly, rolipram can also induce expression of cyclin-dependent kinase (CDK) inhibitors, leading to growth inhibition and differentiation of glioma cells (15), although a high concentration of rolipram was required for these effects. The cAMP-elevating agent forskolin (16), when used at high doses, has been reported to inhibit DNA replication in lymphocytes via PKAmediated effects on p21 CIP1 , leading to dephosphorylation of the retinoblastoma protein (pRb) and disrupted tethering of proliferating cell nuclear antigen to DNA (17).…”