1,721,024 research outputs found
LHRH analogues as anticancer agents: pituitary and extrapituitary sites of action
No full textTwo classes of luteinising hormone-releasing hormone (LHRH) analogues have been developed so far to be used for oncological therapies: LHRH agonists and antagonists. LHRH agonists are widely and successfully used for the management of steroid-dependent malignancies. Chronic administrations of these compounds result in downregulation and desensitisation of pituitary LHRH receptors and, therefore, in a complete suppression of gonadal function. LHRH agonist administration is effective, safe and reversible, suffering only from the 'flare-up' phenomenon at the beginning of treatment. LHRH antagonists suppress the pituitary-gonadal function by competing with native LHRH for binding to its pituitary receptor but without giving rise to the intracellular cascade of events evoked by the natural hormone or LHRH agonists. Synthetic peptides belonging to the last generations of LHRH antagonists have already been successful in clinical trials. They are completely devoid of the 'flare-up' phenomenon and seem to be free of side effects, such as histamine release. Recently, the expression of LHRH and LHRH receptors has been reported in a number of hormone-responsive tumours. In contrast with the pituitary LHRH receptor which is coupled to the Gq/11-PLC intracellular system of events, stimulation of the tumour LHRH receptor by LHRH is followed by the activation of a Gi protein and a decrease in cAMP levels. This intracellular pathway mediates the inhibitory action of the autocrine/paracrine LHRH system on tumour cell proliferation. The activation of LHRH receptors at tumour level may then represent an additional and more direct mechanism of action for the antitumoural activity of LHRH agonists. Surprisingly, LHRH antagonists also exert a marked antimitogenic activity on a number of hormone-responsive cancer cell lines, indicating that these compounds might behave as antagonists at pituitary level and as agonists at the level of the tumour. The observation that the inhibitory LHRH autocrine system is also present in some steroid-unresponsive cancer cell lines might suggest a possible clinical utility of LHRH analogues also for those tumours that have escaped the initial phase of hormone dependency
Al di fuori della cellula: l'adesione e le giunzioni cellulari e le strutture extracellulari
No full text
GnRH agonists sensitize and resensitize, castration-resistant prostate cancer cells to docetaxel : role of the P53 dependent apoptosis pathway
No full textThe biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans
No full textIt is now well known that different forms of GnRH coexist in the same vertebrate species. In humans, two forms of GnRH have been identified so far. The first form corresponds to the hypophysiotropic decapeptide, and is now called GnRH-I. The second form has been initially identified in the chicken brain, and it is referred to as GnRH-II. GnRH-I binds to and activates specific receptors, belonging to the 7 transmembrane (7TM) domain superfamily, present on pituitary gonadotropes. These receptors (type I GnRH receptors) are coupled to the Gq/11/PLC intracellular signalling pathway. A receptor specific for GnRH-II (type II GnRH receptor) has been identified in non-mammalian vertebrates as well as in primates, but not yet in humans. In the last 10-15 years experimental evidence has been accumulated indicating that GnRH-I is expressed, together with its receptors, in tumors of the reproductive tract (prostate, breast, ovary, and endometrium). In these hormone-related tumors, activation of type I GnRH receptors consistently decreases cell proliferation, mainly by interfering with the mitogenic activity of stimulatory growth factors (e.g., EGF, IGF). Recent data seem to suggest that GnRH-I might also reduce the migratory and invasive capacity of cancer cells, possibly by affecting the expression and/or activity of cell adhesion molecules and of enzymes involved in the remodelling of the extracellular matrix. These observations point to GnRH-I as an autocrine negative regulatory factor on tumor growth progression and metastatization. Extensive research has been performed to clarify the molecular mechanisms underlying the peculiar antitumor activity of GnRH-I. Type I GnRH receptors in hormone-related tumors correspond to those present at the pituitary level in terms of cDNA nucleotide sequence and protein molecular weight, but do not share the same pharmacological profile in terms of binding affinity for the different synthetic GnRH-I analogs. Moreover, the classical intracellular signalling pathway mediating the stimulatory activity of the decapeptide on gonadotropin synthesis and secretion is not involved in its inhibitory activity on hormone-related tumor growth. In these tumors, type I GnRH receptors are coupled to the Gi-cAMP, rather than the Gq/11-PLC, signal transduction pathway. Recently, we have reported that GnRH-I and type I GnRH receptors are expressed also in tumors not related to the reproductive system, such as melanoma. Also in melanoma cells, GnRH-I behaves as a negative regulator of tumor growth and progression. Interestingly, the biochemical and pharmacological profiles of type I GnRH receptors in melanoma seem to correspond to those of the receptors at pituitary level. The data so far reported on the expression and on the possible functions of GnRH-II in humans are still scanty. The decapeptide has been identified, together with a 'putative' type II GnRH receptor, both in the central nervous system and in peripheral structures, such as tissues of the reproductive tract (both normal and tumoral). The specific biological functions of GnRH-II in humans are presently under investigation
Gonadotropin-releasing hormone agonists suppress melanoma cell motility and invasiveness throught the inhibition of a3 integrin and MMP-2 expression and activity
No full textAbstract. Cutaneous melanoma represents the leading cause
of skin cancer deaths. The prognosis of highly aggressive,
metastatic melanoma is still very poor, due to the resistance of
the disseminated tumor to existing therapies. The clarification
of the molecular mechanisms regulating melanoma growth
and progression might help identify novel molecular targets
for the development of new therapeutic interventions. We
previously showed that gonadotropin-releasing hormone
(GnRH) receptors are expressed in melanoma cells; activation
of these receptors by means of GnRH agonists significantly
reduces cell proliferation. In the current study, we first showed
that GnRH agonists significantly reduced the metastatic
behavior of melanoma cells in terms of both cell motility
(haptotactic assay using laminin as the chemoattractant) and
invasiveness (cell invasion assay evaluating the capacity of the
cells to invade a reconstituted extracellular matrix barrier). On
the basis of this observation, we then investigated the
molecular mechanisms underlying the antimetastatic activity
of GnRH agonists. We found that, in melanoma cells, a) the
activity of the α3 integrin subunit is crucial for the migratory
behavior of the cells; b) GnRH agonists significantly reduced
α3 integrin expression (Western blotting and immunofluorescence
studies); c) GnRH agonists significantly reduced
MMP-2 expression (comparative RT-PCR) and activity
(zymographic analysis performed on cell culture media).
These data indicate that GnRH agonists, in addition to the
previously reported antiproliferative effect, elicit a strong
inhibitory activity on the migratory/invasive behavior of
melanoma cells expressing GnRH receptors. These compounds
reduce the metastatic potential of melanoma cells by
interfering with the expression/activity of cell adhesion
molecules (α3 integrin) and matrix metalloproteinase
(MMP-2)
Castration Resistant Prostate Cancer : from Emerging Molecular Pathways to Targeted Therapeutic Approaches
No full textAbstract: Prostate cancer is the most commonly diagnosed nonskin cancer and the second leading cause of cancer-related
deaths among men in Western Countries. Most prostate cancers are dependent on androgens for growth and progression in
the early stages. In the case of locally advanced or metastatic prostate cancers the most effective treatment is represented
by androgen ablation therapy, aimed at blocking androgen secretion/activity, such as the so called chemical castration.
This can be achieved either by GnRH agonist monotherapy or by a GnRH agonist in combination with a pure antiandrogen.
Unfortunately, despite an excellent initial response, relapse occurs in approximately 2-3 years with the appearance of
castration resistant prostate cancer (CRPC). Until recently, the only therapy shown to be life prolonging was limited to the
microtubule-stabilizing agent docetaxel. Thus, efforts have been made in order to elucidate the molecular mechanisms underlying
CRPC development with the aim to identify novel molecular targets for effective therapeutic approaches. These
mechanisms include: reactivation of the androgen receptor axis (receptor amplification, mutations, transactivation); tubulin
stabilization and mitotic arrest; development of immunologic tolerance together with the failure of the body's immune
system to elicit antitumor effects; cell survival signaling pathways (clusterin); gonadotropin-releasing hormone (GnRH)
receptors. In this review, we'll focus on the currently available agents targeting these molecular pathways: abiraterone, enzalutamide
(MDV3100), cabazitaxel, sipuleucel-T, custirsen, GnRH analogs and cytotoxic GnRH bioconjugates. Some of
these agents have already received U.S. Food and Drug Administration approval, some are at present under intensive investigation
in preclinical and clinical studies
- …
