The cAMP analog 8‐Cl‐cAMP inhibits growth and induces differentiation and apoptosis in retinoblastoma cells

Abstract

Retinoblastomas appear to be derived from a multipotential stem cell of the retina, due to alterations of the Rb1 gene. These tumors arise only within a discrete time frame during childhood, prior to terminal differentiation of the retinal precursor cells. Treatment of retinoblastoma cells with certain agents can induce a partial differentiation of cell types resembling those of the mature retina, such as rod and cone photoreceptors, glia, conventional neurons and pigment epithelia. We have tested the effects of 8‐Cl‐cAMP, a synthetic analog of cAMP which preferentially binds to and activates the RII subunit of protein kinase A on the Y‐79 retinoblastoma cell line in vitro. Y‐79 cells treated with 8‐Cl‐cAMP produced short, branching processes and showed a substantial increase in staining for neuron‐specific enolase, a marker for conventional neuronal differentiation. In contrast, dibutyryl‐cAMP gives a strong increase in the glial marker glial acidic fibrillary protein. Y‐79 cell proliferation was strongly inhibited by 8‐Cl‐cAMP at concentrations as low as 5–25 μM. 8‐Cl‐cAMP significantly increased the rate of apoptosis of Y‐79 cells in a dose‐dependent manner. It also modulated expression of the RI regulatory subunit of intracellular cAMP‐dependent protein kinase A, which is produced in abnormal quantities by Y‐79 cells. A decrease in protein production was observed, with no clear effect on the RI subunit mRNA expression, suggesting that RI regulation occurs post‐transcriptionally. Int. J. Cancer 72:1088–1094, 1997. © 1997 Wiley‐Liss, Inc.

Gating of the cAMP Signaling Cascade and Melatonin Synthesis by the Circadian Clock in Mammalian Retina

“…For example, cAMP is involved in the regulation of membrane turnover in rod outer segments, cone retinomotor movement, the activity of the G ␤ ␥-binding protein phosducin, and melatonin biosynthesis, as well as some types of retinal degeneration and photoreceptor apoptosis (Besharse et al, 1982;Yoshida et al, 1994;Weiss et al, 1995;Fassina et al, 1997;Alfinito and Townes-Anderson, 2002). The fact that the retinal circadian clock controls the cAMP signaling cascade indicates that this clock has a more general and profound impact on retinal functions than previously thought.…”

Dual Anticancer Activity of 8-Cl-cAMP: Inhibition of Cell Proliferation and Induction of Apoptotic Cell Death

“…In addition, the 8-ClcAMP-induced apoptosis was specific to transformed or cancer cells. The results of phase I clinical trial suggested that effective plasma level of 8-Cl-cAMP could be maintained below the maximum tolerated dose (23), implicating that 8-Cl-cAMP can be used for the treatment of human cancer.…”

8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor

“…8-Chloro-cAMP (8-Cl-cAMP), a synthetic cAMP analogue, is a powerful inhibitor of tumour cell growth both in vivo and in vitro (Tagliaferri et al, 1988;Cho-Chung 1989;Bosanquet et al, 1997; 8-Cl-cAMP antagonizes mitogen-activated protein kinase activation and cell growth stimulation induced by epidermal growth factor Fassina et al, 1997;Tortora et al, 1997b;Langdon et al, 1998). Moreover, phase I clinical studies on 8-Cl-cAMP have been recently completed in cancer patients (Tortora et al, 1995;Saunders et al, 1997).…”