A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity.

Kéri, Gy.; Érchegyi, Judit; Horváth, Anikó; Mezö, Imre; Idei, Miklós; Vántus, Tibor; Balogh, Agnès; Vadász, Zsolt; Bökönyi, Gyöngyi; Seprödi, János; Teplán, István; Csuka, Orsolya; Tejeda, Miguel; Gaál, D.; Szegedi, Z.; Szende, B.; Roze, C; Kalthoff, Holger; Ullrich, Axel

doi:10.1073/pnas.93.22.12513

Cited by 89 publications

(63 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similarly, SST inhibits proliferation and migration of other cancer cells through downregulation of Akt and/ or ERK cascades (Pola et al, 2003;Sun et al, 2007). SST analogs result effective in vivo, inhibiting the growth of induced xenografts and animal tumors (Keri et al, 1996;Kahan et al, 1999), as well as counteracting the growth of neuroendocrine tumors, where they act by downregulating the ERK cascade (Hubina et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

et al. 2011

View full text Add to dashboard Cite

Somatostatin receptors (sst1-5) are present in different types of tumors, where they inhibit key cellular processes such as proliferation and invasion. Although ssts are densely expressed in breast cancer, especially sst2, their role and therapeutic potential remain uncertain. Recently, we identified a new truncated sst5 variant, sst5TMD4, which is related to the abnormal response of certain pituitary tumors to treatment with somatostatin analogs. Here, we investigated the possible role of sst5TMD4 in breast cancer. This study revealed that sst5TMD4 is absent in normal mammary gland, but is abundant in a subset of poorly differentiated human breast tumors, where its expression correlated to that of sst2. Moreover, in the MCF-7 breast cancer model cell, sst5TMD4 expression increased malignancy features such as invasion and proliferation abilities (both in cell cultures and nude mice). This was likely mediated by sst5TMD4-induced increase in phosphorylated extracellular signal-regulated kinases 1 and 2 and p-Akt levels, and cyclin D3 and Arp2/3 complex expression, which also led to mesenchymal-like phenotype. Interestingly, sst5TMD4 interacts physically with sst2 and thereby alters its signaling, enabling disruption of sst2 inhibitory feedback and providing a plausible basis for our findings. These results suggest that sst5TMD4 could be involved in the pathophysiology of certain types of breast tumors.

show abstract

Section: Introductionmentioning

confidence: 99%

The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Unlike somatostatin or conventional somatostatin analogues, TT-232 does not inhibit growth hormone release or gastrin secretion in vivo (4) but it exerts a strong antiproliferative effect and selectively induces caspase-and Bcl-2-independent cell death in a large variety of tumor cells both in vitro and in vivo (4). We have shown previously that TT-232 acts trough seven-pass transmembrane somatostatin receptors to induce G 1 cell cycle arrest (5).…”

Section: Introductionmentioning

confidence: 99%

Nuclear Translocation of the Tumor Marker Pyruvate Kinase M2 Induces Programmed Cell Death

et al. 2007

View full text Add to dashboard Cite

Cancer cells often fail to respond to stimuli that normally activate their intrinsic apoptotic machinery. Moreover, they are able to adapt to hypoxia by changing their glycolytic rate. Pyruvate kinase (PK) is a rate-limiting enzyme in glycolysis that is converted to a less active dimer form of PKM2 isoenzyme during oncogenesis. Here, we show that both somatostatin and the structural analogue TT-232 interact with the PKM subtype. We further show that the PKM2 is translocated to the nucleus in response to TT-232 and different apoptotic agents. Nuclear translocation of PKM2 is sufficient to induce cell death that is caspase independent, isoform specific, and independent of its enzymatic activity. These results show that the tumor marker PKM2 plays a general role in caspaseindependent cell death of tumor cells and thereby defines this glycolytic enzyme as a novel target for cancer therapy development. [Cancer Res 2007;67(4):1602-8]

show abstract

“…However the magnitude of inhibition of PTK activity is similar in all the three peptides (about 45-50% inhibition in PTK activity), in MCF-7 cells. Pawlikowski et al (1998) and Keri et al (1996) have demonstrated that somatostatin analogs mediate their anti-neoplastic effects by the inhibition of PTK activity, in several carcinomas. [34][35][36] The activation of protein tyrosine phosphatase, by SSTR2 has been recognized as one of the predominant signaling mechanisms mediating cell growth arrest (via SSTRs 1, 2, 4, or 5) or apoptosis (via SSTR3).…”

Section: Discussionmentioning

confidence: 99%

N-Terminal Acylation of Somatostatin Analog with Long Chain Fatty Acids Enhances Its Stability and Anti-Proliferative Activity in Human Breast Adenocarcinoma Cells.

Dasgupta

Singh

Mukherjee

2002

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The therapeutic potential of peptide drugs has remained unfulfilled due to the unfavorable physicochemical properties of these molecules. Peptides are extremely susceptible to proteolytic degradation in blood and tissues. The hydrophilic nature of peptides severely limits their permeability across hydrophobic cell membranes.2) RC-160, a potent somatostatin analog is one of the most extensively studied therapeutic peptides for its anti-proliferative and anti-secretory activity.D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH 2 Compared to somatostatin, RC-160 possesses improved anti-proliferative and anti-secretory activity. It is particularly active against breast, prostate, renal and ductal pancreatic cancers and has been successfully used in the therapy of hypersecretory states and AIDS-related diarrhea.3-5) Despite the high potency and specificity of RC-160, its application as a clinically useful drug has been problematic because of its short biological half-life and serious delivery problems. The bioactivity of RC-160 is mediated through high affinity Gprotein coupled somatostatin receptors (SSTRs) on target cells. 4,5) It has been suggested that the inhibitory effect of RC-160 on tumor growth may be mediated directly by SSTRs on cancer cells, or induced indirectly by the inhibition of growth factors such as epidermal growth factor (EGF), insulin like growth factor (IGF)-1, etc. [3][4][5] Although somatostatin analogs like octreotide and RC-160 are longer acting than the native hormone, their biological activity of less than 2 h requires either frequent administration, or sustained release formulation, to attain enhanced anti-proliferative activity and a long-term suppression of hormones like growth hormone (GH) and IGF-1. 6) Formulations of octreotide and somatuline, made by entrapping the peptide in DL-lactide-co-glycollide polymer microspheres 6-10) have been shown to display improved anti-proliferative activity and modulation of GH release but their pharmacokinetic properties are not optimal. 7,8) Somatuline displays an initial burst in drug release whereas octreotide produces an initial delay in peptide release. The administration of these antitumor agents is also limited by their pleotropic nature and side effects like increased incidence of cholesterol gallstones, temporary inhibition and/or delay of insulin release in response to meals and diminished in glucose tolerance in some patients.11) The acute administration of somatostatin agonists has been observed to produce receptor desensitization, which results in diminished therapeutic response and induction of tolerance.11) Hence, there is a need for further modification of these analogs to increase their stability and improve their therapeutic index.Lipophilization (conjugation of fatty acyl moiety) of bioactive peptides, is a novel strategy to increase their stability and biological availability. Unlike sustained release formulations, lipophilization can also impart enhanced receptor selectivity to peptides. [12][13][14] The attachment of fatty acids to pepti...

show abstract

A tumor-selective somatostatin analog (TT-232) with strong in vitro and in vivo antitumor activity.

Cited by 89 publications

References 34 publications

The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

The new truncated somatostatin receptor variant sst5TMD4 is associated to poor prognosis in breast cancer and increases malignancy in MCF-7 cells

Nuclear Translocation of the Tumor Marker Pyruvate Kinase M2 Induces Programmed Cell Death

N-Terminal Acylation of Somatostatin Analog with Long Chain Fatty Acids Enhances Its Stability and Anti-Proliferative Activity in Human Breast Adenocarcinoma Cells.

Contact Info

Product

Resources

About