1.The somatostatin analogue TT-232 induces apoptosis in A431 cells: sustained activation of stress-activated kinases and inhibition of signalling to extracellular signal-regulated kinases.
Vántus T;Kéri G;Krivickiene Z;Valius M;Steták A;Keppens S;Csermely P;Bauer PI;Bökönyi G;Declercq W;Vandenabeele P;Merlevede W;Vandenheede JR Cell Signal. 2001 Oct;13(10):717-25.
TT-232 is a somatostatin analogue containing a five-residue ring structure. The present report describes TT-232-induced signalling events in A431 cells, where a 4-h preincubation with the peptide irreversibly induced a cell death program, which involves DNA-laddering and the appearance of shrunken nuclei, but is unrelated to somatostatin signalling. Early intracellular signals of TT-232 include a transient two-fold activation of the extracellular signal-regulated kinase (ERK2) and a strong and sustained activation of the stress-activated protein kinases c-Jun NH(2)-terminal kinase (JNK)/SAPK and p38MAPK. Blocking the signalling to ERK or p38MAPK activation had no effect on the TT-232-induced cell killing. At the commitment time for inducing cell death, TT-232 decreased EGFR-tyrosine phosphorylation and prevented epidermial growth factor (EGF)-induced events like cRaf-1 and ERK2 activation. Signalling to ERK activation by FCS, phorbol 12-myristate 13-acetate (PMA) and platelet-derived growth factor (PDGF) was similarly blocked. Our data suggest that TT-232 triggers an apoptotic type of cell death, concomitant with a strong activation of JNK and a blockade of cellular ERK2 activation pathways.
2.TT-232: a somatostatin structural derivative as a potent antitumor drug candidate.
Szende B;Kéri G Anticancer Drugs. 2003 Sep;14(8):585-8.
TT-232 (D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2) has been developed as an antitumor somatostatin analog. TT-232 has no growth hormone release inhibitory effect and does not inhibit the secretion of gastric acid. This analog induces apoptosis in and exerts pronounced antiproliferative effects on various human tumors (colon, pancreas, lymphoma, leukemia, melanoma, hepatoma) cell lines. The growth of human xenografts (prostate, breast carcinoma, lymphoma, melanoma) and animal tumors (colon-26, P-388, S-180, B16, MXT) was inhibited by TT-232 (dose range: 30-750 microg/kg/day) in 54-98% of cases. Continuous long-term infusion proved to be the most effective way of administration. TT-232 combined with decarbazine or etoposide treatment enhanced the antitumor activity of these drugs on human melanoma and lymphoma xenografts, respectively. Regarding the mode of action, TT-232 activates cell cycle inhibitors via SSTR receptors, inhibits tyrosine kinases through interfering with the proliferative signaling cascades, and interacts with an intracellular receptor and an enzyme involved in glycolysis causing translocation of this enzyme to the nucleus, thus inducing apoptosis. TT-232 may be a promising candidate in the therapy of human malignancies.
3.A new strategy for the synthesis of cyclopeptides containing diaminoglutaric acid.
Bayer T;Riemer C;Kessler H J Pept Sci. 2001 May;7(5):250-61.
A new synthesis of orthogonally protected diaminoglutaric acid containing peptides using the Ugi four component condensation is presented. To demonstrate that this method is useful to replace cystine by diaminoglutaric acid in biologically interesting peptides, we built up two cyclic somatostatin analogues deriving from Sandostatin and from TT-232. A photolytically cleavable amine derivative of the nitroveratryl type is used for the Ugi four component condensation. Because of a racemic build up of the new stereocentre of the diaminoglutaric acid, and racemization of the isonitrile component, four diastereomeric peptides resulted that were separated by HPLC. The stereochemistry of the cyclopeptides could be easily and unambiguously assigned by chiral gas chromatography and a reference sample of enantiomerically pure (2S,4S)-diaminoglutaric acid.
