Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative

Lanzi, Cinzia; Cassinelli, Giuliana; Pensa, Tiziana; Cassinis, Marco; Gambetta, Romolo A.; Borrello, Maria Grazia; Menta, Ernesto; Pierotti, Marco A.; Zunino, Franco

doi:10.1002/(sici)1097-0215(20000201)85:3<384::aid-ijc15>3.3.co;2-p

Cited by 4 publications

(7 citation statements)

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“…Indeed, the function of inappropriately activated protein tyrosine kinases can be inhibited by specific inhibitors, as already documented [14]. In a previous paper, we described the inhibitory activity of the 2-indolinone derivative RPI-1 (formerly Cpd1) against Ret/Ptc1 kinase and the RET/PTC1 oncogene 1450 C. Lanzi et al Inactivation of Ret/ptc1 oncoprotein transforming ability in NIH3T3 mouse fibroblasts [15].…”

mentioning

confidence: 66%

“…These findings raise the question of the functional role of the single Shc isoforms in Ret signaling, an aspect that has not been addressed up to now. The drug-induced down-regulation of p66Shc was an unexpected finding since it was not observed in NIH3T3 PTC1 cells [15]. Such an Shc isoform, indeed, does not appear to be involved in Research Article the Ras/ERK pathway but has been proposed as a cytoplasmic signal transducer involved in stress apoptotic responses and life span in mammals [42,43].…”

Section: Discussionmentioning

confidence: 97%

“…fig. 2 A), reminiscent of the reversion of the transformed phenotype induced by the drug in NIH3T3 PTC1 transfectants [15]. The selectivity of RPI-1 for TPC-1 cells was also maintained in low-serum (0.5 %) culture conditions (not shown).…”

Section: Telomerase Activity Detection Assay and Rt-pcr Analysis Of Tmentioning

confidence: 94%

“…For immunoprecipitation experiments, control and treated cells were processed as previously described [15]. For whole-cell extract preparation, cells were lysed in sodium dodecyl sulfate (SDS) sample buffer [62.5 mM Tris-HCl (pH 6.8), 2 % SDS] with 1 mM PMSF, 10 mg/ ml pepstatin, 12.5 mg/ml leupeptin, 100 KIU aprotinin, 1 mM sodium orthovanadate, 1 mM sodium molybdate.…”

Section: Immunoprecipitation and Western Blottingmentioning

confidence: 99%

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Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1

Lanzi

Cassinelli

Cuccuru

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

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Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could thereby represent a specific therapeutic approach. We previously described the inhibitory activity of the 2-indolinone derivative RPI-1 (formerly Cpdl) on the tyrosine kinase activity and transforming ability of the products of the RET/PTC1 oncogene exogenously expressed in murine cells. In the present study, we investigated the effects of RPI-1 in the human papillary thyroid carcinoma cell line TPC-1 spontaneously harboring the RET/PTC1 rearrangement. Treatment with RPI-1 inhibited cell proliferation and induced accumulation of cells at the G2 cell cycle phase. In treated cells, Ret/Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase C(gamma), thereby indicating abrogation of constitutive signaling mediated by the oncoprotein. Activation of JNK2 and AKT was abolished, thus supporting the drug inhibitory efficacy on downstream pathways. In addition, cell growth inhibition was associated with a reduction in telomerase activity by nearly 85%. These findings in a cellular context relevant to the pathological function of RET oncogenes support the role of Ret oncoproteins as useful targets for therapeutic intervention, and suggest RPI-1 as a promising candidate for preclinical development in the treatment of thyroid tumors expressing RET oncogenes.

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confidence: 66%

Section: Discussionmentioning

confidence: 97%

Section: Telomerase Activity Detection Assay and Rt-pcr Analysis Of Tmentioning

confidence: 94%

Section: Immunoprecipitation and Western Blottingmentioning

confidence: 99%

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Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1

Lanzi

Cassinelli

Cuccuru

et al. 2003

Cellular and Molecular Life Sciences (CMLS)

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“…ZD6474 is also a potent inhibitor of KDR, the vascular endothelial growth factor (VEGF) receptor, and thus exerts anti-angiogenic effects [90]. The arylidene 2-indolinone RPI-1 was effective against RET but only at high doses (IC 50 in the micromolar range) [91]. Two indolocarbazole derivatives, CEP-701 and CEP-751, inhibit RET-MEN 2A oncoproteins at concentrations <100 nM.…”

Section: Ret As a Target For Therapeutic Interventionmentioning

confidence: 99%

Oncogenic protein tyrosine kinases

Santoro

Carlomagno

Melillo

et al. 2004

CMLS, Cell. Mol. Life Sci.

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RET is the receptor for glial-derived neurotrophic factor growth factors. It is a paradigm of a single gene that causes different types of human cancer when targeted by different genetic alterations. Like other receptor tyrosine kinases, once activated, RET recruits a variety of signaling molecules that mediate biological responses. Here we review data on the signaling pathways that lead to RET-mediated cell transformation and recent evidence that manipulation of RET holds promise for thyroid cancer treatment.

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Partial remission of metastatic papillary thyroid carcinoma with sunitinib. Report of a case and review of the literature

Kaldrymides

Kostoglou-Athanassiou

Gkountouvas

et al. 2010

Endocr

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Tyrosine kinase receptors have been implicated in thyroid cancer. Therefore, tyrosine kinase inhibitors may be used for the treatment of advanced metastatic thyroid carcinoma. The aim is to present a case of metastatic papillary thyroid carcinoma responding to the administration of sunitinib, a multi-targeted protein kinase inhibitor. A patient presented with metastatic papillary thyroid carcinoma and hyperthyroidism. After euthyroidism was achieved the patient was treated by the administration of therapeutic radioiodine (131)I, radiotherapy and sunitinib, a multi-targeted tyrosine kinase inhibitor. Thyroglobulin levels decreased from 9,594 to 6,816 ng/ml after 1 month, 6 months later being 2,776 ng/ml. The lesion in the pelvis was 12.5 × 9 cm before treatment decreasing thereafter and the patient improved clinically. The administration of sunitinib resulted in partial disease response in a patient with progressive metastatic papillary thyroid carcinoma. Protein kinase inhibitors may prove useful in the management of advanced metastatic papillary thyroid carcinoma.

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Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative

Cited by 4 publications

References 0 publications

Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1

Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1

Oncogenic protein tyrosine kinases

Partial remission of metastatic papillary thyroid carcinoma with sunitinib. Report of a case and review of the literature

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