American Association of Endocrine SurgeonsNeuroendocrine tumor cell growth inhibition by ZM336372 through alterations in multiple signaling pathways
Section snippets
Cell culture
TT and human bronchopulmonary carcinoid (H727) cells were obtained from ATCC and maintained in RPMI 1640 (Invitrogen, Carlsbad, CA) supplemented with fetal bovine serum (Sigma, St. Louis, MO), 100 IU/mL penicillin, and 100 μg/mL streptomycin (Invitrogen) in a humidified atmosphere of 5% CO2 in air at 37°C as described.4, 11, 14
ZM336372 treatment
TT or H727 cells were plated onto 100-mm dishes. The following day, media was changed to fresh media containing varying concentrations of ZM336372 (0 to 200 μmol/L) and
ZM336372 inhibits cellular growth in TT cells
We have reported that treatment of carcinoid cells (BON and H727) with ZM336372 resulted in activation of raf-1 pathway that was associated with growth inhibition.13 Furthermore, we reported recently that inhibition of pheochromocytoma (PC12) cell growth in vitro by ZM336372 was shown to be associated with raf-1 pathway activation15; however, the effect of ZM336372 on the growth of TT cells is not known. We have done cytotoxic experiment with different cell lines including TT and observed that,
Discussion
NENs such as MTC and carcinoid neoplasms represent a diverse group of neoplasms with unique clinical presentations. NENs metastasize frequently to distant organs. Endocrinopathies related to the production of various amines and peptides from these neoplasms can result in debilitating symptoms. Operative resection is the only curative therapy for patients with NENs, but complete resection is often not possible owing to the metastatic nature of the disease. Therefore, there is a great need for
References (15)
- et al.
Hairy Enhancer of Split-1 (HES-1), a Notch1 effector, inhibits the growth of carcinoid tumor cells
Surgery
(2005) - et al.
The role of human achaete-scute homolog-1 in medullary thyroid cancer cells
Surgery
(2003) - et al.
Carcinoid tumors
Surg Oncol Clin North Am
(2006) - et al.
Apoptosis mediated medullary thyroid cancer growth suppression by the PI3K inhibitor LY294002
Surgery
(2006) - et al.
Over expression of the Notch1 intracellular domain (NICD) inhibits cellular proliferation and alters the neuroendocrine phenotype of medullary thyroid cancer cells
J Biol Chem
(2006) - et al.
ZM336372, a Raf-1 activator, inhibits growth of pheochromocytoma cells
J Surg Res
(2006) - et al.
Inactivation of glycogen synthase kinase-3beta, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells
Mol Cancer Ther
(2007)
Cited by (19)
ZM336372 Induces Apoptosis Associated with Phosphorylation of GSK-3β in Pancreatic Adenocarcinoma Cell Lines
2010, Journal of Surgical ResearchCitation Excerpt :We have shown in neuroendocrine cell lines that down-regulation of neuroendocrine markers is independent of the raf-1/MEK/ERK pathway [15]. Most importantly, the GSK-3β inhibition by ZM336372 was shown to be required for neuroendocrine phenotype reduction [15]. This suggests that the GSK-3β inhibition has greater significance in relation to the suppression of cellular proliferation due to ZM336372 treatment.
MG-132 Inhibits Carcinoid Growth and Alters the Neuroendocrine Phenotype
2010, Journal of Surgical ResearchCitation Excerpt :There is also a growing body of literature suggesting that methods to inactivate GSK-3β in NE cancer cells may be a novel treatment approach [11, 14, 22, 23]. We have previously reported that in medullary thyroid cancer, pheochromocytoma, and carcinoid cancer cells, treatment with ZM-336372 and lithium chloride inhibits GSK-3β signaling, and is associated with inhibition of cellular growth and a change in the NE phenotype [14, 23]. These results suggest that inactivation of GSK-3β may be a potential therapeutic target for carcinoid disease.
MAP kinase: It's been longer than fifteen minutes
2008, Biochemical and Biophysical Research CommunicationsCitation Excerpt :In small cell cancer of the lung, mutations inactivate Raf-1 and reintroduction of active Raf-1 inhibits growth and causes differentiation [23]. This has potential because a Raf-1 activator (ZM336372) inhibits carcinoid tumors [24]. Although v-Ras-induced senescence is blocked by PD98059 and mimicked by active MEK1-EE, how the ERK MAP kinases immediately downstream are involved is unclear.
GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors
2018, NeuroendocrinologyTropomyosin receptor kinase: A novel target in screened neuroendocrine tumors
2018, Endocrine-Related CancerTargeted therapy of gastroenteropancreatic neuroendocrine tumours: Preclinical strategies and future targets
2018, Endocrine Connections
Supported in part by a Research Scholars Grant from the American Cancer Society, National Institutes of Health grants DK064735, DK066169 and CA109053; the George H.A. Clowes, Jr., Memorial Research Career Development Award of the American College of Surgeons, the Carcinoid Cancer Foundation Award (HC) the University of Wisconsin Medical School Grant (MK); and the Robert Draper Technology Innovation award (MK).