Imatinib inhibits spontaneous rhythmic contractions of human uterus and intestine

Popescu, L. M.; Vidulescu, Cristina; Curici, Antoanela; Caravia, Laura; Simionescu, Anca Angela; Ciontea, Sanda M.; Simion, S

doi:10.1016/j.ejphar.2006.06.068

Cited by 75 publications

(66 citation statements)

References 27 publications

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“…These are c-Kit-expressing cells that may be related to the interstitial Cajal cells of the gut, which mediate rhythmic activity in smooth muscle cells (40). The activity of these cells can be inhibited by imatinib (41).…”

Section: Discussionmentioning

confidence: 99%

The naïve airway hyperresponsiveness of the A/J mouse is Kit -mediated

Cozzi¹,

Ackerman²,

Lundequist

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

The naïve airway hyperresponsiveness of the A/J mouse is Kit -mediated

Cozzi¹,

Ackerman²,

Lundequist

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In various other smooth muscles, imatinib predominantly reduces the amplitude of spontaneous contractions without altering their frequency. 12,13) Recently, Hashitani et al 15) suggested that imatinib inhibited the slow wave but not inhibited the frequency in the guinea pig corpus. Therefore, we think that this phenomenon is specific to imatinib and imatinib may not affect the initial component of pacemaker potentials.…”

Section: Discussionmentioning

confidence: 99%

“…10) As both development and maintenance of ICC require Kit, 11) an inhibitor of Kit signaling could be used as a specific blocker for the function of ICC. Recently, imatinib mesylate has been shown to suppress contractile activity in various phasic smooth muscles, including the human uterus and small intestine, 12) guinea-pig bladder, 13) guinea-pig gall bladder 14) and guinea pig stomach. 15) However, none of the studies has demonstrated that the effects of imatinib mesylate, on pacemaker potentials in ICC.…”

mentioning

confidence: 99%

Effects of Imatinib Mesylate in Interstitial Cells of Cajal from Murine Small Intestine

Kim

Chae

Kwon

et al. 2010

Biological & Pharmaceutical Bulletin

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The interstitial cells of Cajal (ICCs) are pacemakers in the gastrointestinal tract. The possibility of whether imatinib mesylate, a Kit receptor tyrosine kinase inhibitor, modulates pacemaker activities in the ICC was examined using the whole cell patch clamp technique. Imatinib decreased the amplitude of pacemaker potentials in a dose-dependent manner in current-clamp mode. Because the effects of imatinib on pacemaker potentials were the same as those of pinacidil, we examined the effect of glibenclamide on ICC exposed to imatinib. The effects of imatinib on pacemaker potentials were blocked by glibenclamide. To see whether the production of prostaglandins (PGs) is involved in the inhibitory effect of imatinib on pacemaker potentials, we tested the effects of naproxen (a non-selective cyclooxygenase inhibitor) and AH6809 (a prostaglandin EP1 and EP2 receptor antagonist). Naproxen and AH6809 blocked the inhibitory effects of imatinib on ICC. Butaprost (an EP2 receptor agonist) showed the actions on pacemaker potentials in the same manner as imatinib. However, SC 19220 (an EP1 receptor antagonist) has no effects. To investigate the involvement of cAMP and protein kinase A (PKA) in the effects of imatinib on ICC, SQ 22536 (an inhibitor of adenylate cyclase) and mPKAI (an inhibitor of myristoylated PKA) were used. Both SQ-22536 and mPKAI blocked the imatinib-mediated inhibition of pacemaker potentials. However, the protein kinase C (PKC) inhibitors did not block the imatinib-mediated inhibition of pacemaker potentials. These results indicate that imatinib inhibits the pacemaker potentials of ICC by activating ATP-sensitive K ؉ ؉ channels and PKA-dependent, PKC-independent manner.

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“…Recently STI571 (Glivec, Novartis, Basel, Switzerland), a tyrosine kinase inhibitor, was found to have a favorable therapeutic effect on metastatic GIST and c-Kit expression in tumor cells became an important criterion in the diagnosis as well as the management of GIST [67][68][69]. Moreover, Glivec was proved to inhibit spontaneous rhythmic contractions of human intestine and also in human uterus, perhaps via ligand-independent c-kit/CD117 tyrosine-kinase signaling [70].…”

Section: Molecular Biology Of Iccmentioning

confidence: 99%

Interstitial Cells of Cajal (ICC) and Gastrointestinal Stromal Tumor (GIST): facts, speculations, and myths

Min

Leabu

2006

Journal of Cellular and Molecular Medicine

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Interstitial cells of Cajal (ICC) is a peculiar cell network composed of cells having processes described by the eminent Spanish neuroanatomist of the 19 th century, S. Ramon y Cajal. ICC became a fascinating subject to many investigators and it is estimated that there are over 100 publications yearly on the subject related to ICC, in the last three years. Now it is widely accepted that ICC are pace maker cells of the gut and probable progenitor cells of gastrointestinal stromal tumors (GIST). Lately, interstitial Cajal-like cells (ICLC) are being found in various organs and their physiological role is still to be defined. We have reviewed the literature trying to evaluate the validity of the current concept and found that there are a few salient points to be considered. 1) There has been some important departure in defining the identity of ICC from the original criteria of Cajal. In particular, ICC with myoid feafures in intestinal smooth muscle layers (ICC-DPM) do not seem to fit to the original description of interstitial cell network by Cajal. We have also pointed out that the current reports assigning a pace maker role to ICC vastly depend on the scientific data on "ICC with myoid features", not on "fibroblast-like ICC", which are more abundant and easier to identify. 2) There seem to be an overwhelming amount of data proving the relationship between ICC and GIST. Both are known to express c-Kit and the ultrastructural characteristics seen in GIST roughly parallel those of ICC including minimal myoid differentiation seen in the majority of GIST, supporting the current concept that GIST are ICC tumors. 3) According to the original description of Cajal, ICC was not limited to the gut, suggesting an existence of ICC in other organs. The list of organs reported to contain ICC (currently identified by immunohistochemistry and electron microscopy) is ever growing and further studies are needed to define their identity and pathophysiologic role. 4). Recent data concerning gut development suggest that both c-Kit expressing ICC (fibroblasts-like as well as muscle-like) and gut muscle cells Their physiologic role was not clear at that time and even today, but Cajal speculated on a possible ancillary neural function, because of their anatomic proximity and morphologic similarity to nerves. In fact, interstitial cells of the gut are neither neural nor muscular, but are interposed between nerve and muscle cells. He considered that they might play a controlling function of the gut motility, and he thereby stimulated many investigators to study his concept. Consequently, a vast amount of data has been accumulated on 1) their existence, 2) the ultrastructural characterization of a possible pacemaker role in the gut, 3) electrophysiologic studies of peristalsis, 4) c-Kit as a molecular marker of ICC, and 5) as progenitor cells of gastrointestinal stromal tumors (GIST). The data thus far accumulated is vast and complex, but has promulgated the definition and identification of ICC [19].In recent years, much interesti...

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Imatinib inhibits spontaneous rhythmic contractions of human uterus and intestine

Cited by 75 publications

References 27 publications

The naïve airway hyperresponsiveness of the A/J mouse is Kit -mediated

The naïve airway hyperresponsiveness of the A/J mouse is Kit -mediated

Effects of Imatinib Mesylate in Interstitial Cells of Cajal from Murine Small Intestine

Interstitial Cells of Cajal (ICC) and Gastrointestinal Stromal Tumor (GIST): facts, speculations, and myths

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