Antiproliferative activity induced by the somatostatin analogue, TT-232, in human pancreatic cancer cells.
Somatostatin analogues have been developed as antiproliferative agents, but their administration as general antitumour agents is limited, mainly because of the wide distribution of somatostatin receptors throughout the human body. TT-232, a new somatostatin structural analogue, was reported to have tumour-selective antiproliferative activity without an antisecretory action. We examined whether TT-232 had antiproliferative activity in human pancreatic cancer cell lines, and compared its antiproliferative activity with that of RC-160 and other TT-232 derivatives. TT-232 inhibited the growth of all of the cell lines used in this study and induced apoptotic cell death. RC-160 showed no such growth inhibition. TT-232 also inhibited tumour formation in a xenograft model. A competitive binding assay was performed using the cell membrane fraction and 111In-DTPA-TT-232 in order to show the existence of a specific binding site on the cells. A specific binding site was detected in MIAPaCa-2 cells. It has been shown that the activation of protein tyrosine phosphatase (PTPase) is one of the main intracellular pathways responsible for somatostatinergic inhibition of cell growth. We found a significant PTPase stimulation after TT-232 administration using an immunoblot analysis assessing the level of protein tyrosine phosphorylation, and also a direct measurement of the PTPase activity. We also demonstrated that PTPase stimulation by TT-232 was involved in its antiproliferative activity as this activity was reversed by the addition of sodium orthovanadate, a PTPase inhibitor. Our results indicate that TT-232 could be a potentially useful therapeutic agent if these data are translated into clinical practice.
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto, University, 54 Shogoin-Kawaracho, Sakyo, 606-8507, Kyoto, Japan.
J-U
JU
Lee
R
R
Hosotani
M
M
Wada
R
R
Doi
T
T
Koshiba
K
K
Fujimoto
Y
Y
Miyamoto
S
S
Tsuji
S
S
Nakajima
M
M
Hirohashi
T
T
Uehara
Y
Y
Arano
N
N
Fujii
M
M
Imamura
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives*; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D014638:Vanadates; C094462:TT2-32; D013004:Somatostatin; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases