Somatostatin–dopamine ligands in the treatment of pituitary adenomas

Saveanu, Alexandru; Jaquet, P

doi:10.1007/s11154-008-9086-0

Cited by 34 publications

(20 citation statements)

References 75 publications

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“…However, distinct differences in response to these ligands, either alone or in combination, across both individual adenomas and also particular subtypes are apparent. Despite these observations, chimeric compounds with affinity for SST and D2 receptors have in some cases been shown to act synergistically in the control of secretion and/or proliferation of different pituitary adenoma subtypes [44,45]. Employing apoptosis as a functional end-point our study shows that DA and BC utilise different intracellular apoptotic cascades and these findings promoted us to examine the effects of these drugs in co-incubation experiments.…”

Section: Discussionmentioning

confidence: 93%

Bromocriptine and Dopamine Mediate Independent and Synergistic Apoptotic Pathways in Pituitary Cells

Rowther

Richardson²,

Clayton³

et al. 2010

Neuroendocrinology

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Dopamine (DA) agonists are the primary treatment choice for prolactinoma, effectively suppressing prolactin expression and reducing tumour size. However, the intracellular pathway(s) through which either DA or its agonists impact on proliferation or lead to tumour shrinkage are incompletely understood. To identify the mediators in the apoptotic cascades after DA or DA agonist challenges we used a well-characterized model system, the rodent somatolactotroph cell line GH3. In these cells, we show that apoptosis induced by the DA agonist bromocriptine (BC), but not DA, is initiated through activation of the JNK pathway. However, both DA and BC activate the terminal effector caspase, caspase-3. Kinetic studies and chemical inhibitor co-incubation experiments support a role for JNK activation preceding caspase-9 activation in BC challenged cells, however, engagement of these mediators was not apparent in DA challenge cells. These studies suggest that apoptosis induced by BC or DA is mediated through distinct and independent pathways that converge with activation of the terminal caspase, caspase-3. These observations were further reinforced by our findings that DA and BC, in co-incubation experiments, synergistically induce apoptosis. These findings raise the possibility that drugs acting through the same pathway as DA may be clinically beneficial when combined with BC.

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Section: Discussionmentioning

confidence: 93%

Bromocriptine and Dopamine Mediate Independent and Synergistic Apoptotic Pathways in Pituitary Cells

Rowther

Richardson²,

Clayton³

et al. 2010

Neuroendocrinology

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“…Co-expression of SSTR and D 2 in pituitary adenomas has been recently reviewed extensively (Jaquet et al 2005b, Ferone et al 2009, Saveanu & Jaquet 2009). Here, we would like to underline few important aspects: the D 2 receptor is the GPCR mostly represented in the pituitary tumors, overall it is associated with two or more SSTR subtypes (preferentially sst 2 and sst 5 ), and there is a high variability in SSTR and D 2 expression due to the heterogeneity of these tumors (Zatelli et al 2005, Ferone et al 2008, Saveanu et al 2008, de Bruin et al 2009c.…”

Section: Ss and Da Receptor Co-expression In Endocrine Tumorsmentioning

confidence: 99%

The role of somatostatin and dopamine D2 receptors in endocrine tumors

Gatto¹,

Hofland²

2011

Endocrine-Related Cancer

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Somatostatin (SS) and dopamine (DA) receptors have been highlighted as two critical regulators in the negative control of hormonal secretion in a wide group of human endocrine tumors. Both families of receptors belong to the superfamily of G protein-coupled receptors and share a number of structural and functional characteristics. Because of the generally reported high expression of somatostatin receptors (SSTRs) in neuroendocrine tumors (NET), somatostatin analogs (SSA) have a pronounced role in the medical therapy for this class of tumors, especially pituitary adenomas and well-differentiated gastroenteropancreatic NET (GEP NET). Moreover, NET express not only SSTR but also frequently dopamine receptors (DRs), and DA agonists targeting the D 2 receptor (D 2 ) have been demonstrated to be effective in controlling hormone secretion and cell proliferation in in vivo and in vitro studies. The treatment with SSAs combined with DA agonists has already been demonstrated efficacious in a subgroup of patients with GH-secreting pituitary adenomas and few reported cases of carcinoids. The recent availability of new selective and universal SSA and DA agonists, as well as the chimeric SS/DA compounds, may shed new light on the potential role of SSTR and D 2 as combined targets for biotherapy in NET. This review provides an overview of the latest studies evaluating the expression of SSTR and DR in NET, focusing on their co-expression and the possible clinical implications of such co-expression. Moreover, the most recent insights in SSTR and D 2 pathophysiology and the future perspectives for treatment with SSA, DA agonists, and SS/DA chimeric compounds are discussed.

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“…In this study, we have used two tumor cell lines constitutively expressing four (LNCaP) and three (Calu-6) out of the five SRIF receptors (Ferone et al 2005, Ruscica et al 2010) and the D 2 R. These non-neuroendocrine cell lines, because of their constitutive and relatively low receptor expression, represent a useful model to investigate the physiological mechanisms involved in protein membrane interaction, such as receptor dimerization. Since recently new SRIF analogues with a specific affinity for given receptor subtypes, and SRIF/DA chimeric compounds have been developed (Ferone et al 2005, Saveanu & Jaquet 2009, in this study we have investigated the effect of these compounds on receptor interaction, and correlated the occurrence of co-immunoprecipitated receptors with the impact on cell proliferation. Since we already demonstrated a dose-response effect of these compounds in the inhibition of cell proliferation (Ferone et al 2005), in this study, we have performed all experiments using the concentration of compounds that demonstrated about a 50% inhibitory effect (10 K9 M).…”

Section: Discussionmentioning

confidence: 99%

Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines

Arvigo¹,

Gatto²,

Ruscica³

et al. 2010

Journal of Endocrinology

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Somatostatin analogues inhibit in vitro cell proliferation via specific membrane receptors (SSTRs). Recent studies on transfected cell lines have shown a ligand-induced formation of receptor dimers. The aim of this study is 1) to evaluate the role of specific ligands in modulating receptor interactions in the androgen-dependent prostate cancer cell line, LNCaP, and in the non-small cell lung cancer line, Calu-6, by co-immunoprecipitation and immunoblot; and 2) to correlate the antiproliferative effect of these compounds with their ability in modulating receptor interactions. In LNCaP, we have demonstrated the constitutive presence of sstr 1 /sstr 2 , sstr 2 /sstr 5 , sstr 5 /dopamine (DA) type 2 receptor (D 2 R), and sstr 2 /D 2 R dimers. BIM-23704 (sstr 1 -and sstr 2 -preferential compound) increased the co-immunoprecipitation of sstr 1 /sstr 2 and significantly inhibited proliferation (K30 . 98%). BIM-23244 (sstr 2 -sstr 5 selective agonist) significantly increased the co-immunoprecipitation of sstr 2 /sstr 5 , and induced a K41 . 36% inhibition of proliferation. BIM-23A760, a new somatostatin/DA chimeric agonist with a high affinity for sstr 2 and D 2 R and a moderate affinity for sstr 5 , significantly increased the sstr 5 /D 2 R and sstr 2 /D 2 R complexes and was the most powerful in inhibiting proliferation (K42 . 30%). The chimeric compound was also the most efficient in modulating receptor interaction in Calu-6, increasing the co-immunoprecipitation of D 2 R/sstr 5 and inhibiting cell proliferation (K30 . 54%). However, behind BIM-23A760, BIM-53097 (D 2 R-preferential compound) also significantly inhibited Calu-6 proliferation (K17 . 71%), suggesting a key role for D 2 R in receptor cross talk and in controlling cell growth. Indeed, activation of monomeric receptors did not affect receptor co-immunoprecipitation, whereas cell proliferation was significantly inhibited when the receptors were synergistically activated. In conclusion, our data show a dynamic ligand-induced somatostatin and DA receptor interaction, which may be crucial for the antiproliferative effects of the new analogues.

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Somatostatin–dopamine ligands in the treatment of pituitary adenomas

Cited by 34 publications

References 75 publications

Bromocriptine and Dopamine Mediate Independent and Synergistic Apoptotic Pathways in Pituitary Cells

Bromocriptine and Dopamine Mediate Independent and Synergistic Apoptotic Pathways in Pituitary Cells

The role of somatostatin and dopamine D2 receptors in endocrine tumors

Somatostatin and dopamine receptor interaction in prostate and lung cancer cell lines

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