Comparison of the Tyrosine Kinase Activity with the Proliferation Rate in Human Colon Solid Tumors and Tumor Cell Lines

Background: Dimedone and thiazole moieties are privileged scaffolds (acting as primary pharmacophores) in many compounds that are useful to treat several diseases, mainly tropical infectious diseases. Thiazole derivatives are a very important class of compounds due to their wide range of pharmaceutical and therapeutic activities. On the other hand, dimedone is used to synthesize many therapeutically active compounds. Therefore, the combination of both moieties through a single molecule to produce heterocyclic compounds will produce excellent anticancer agents. Objective: The present work reports the synthesis of 47 new substances belonging to two classes of compounds: Dimedone and thiazoles, with the purpose of developing new drugs that present high specificity for tumor cells and low toxicity to the organism. To achieve this goal, our strategy was to synthesize a series of 4,5,6,7-tetrahydrobenzo[d]-thiazol-2-yl derivatives using the reaction of the 2-bromodimedone with cyanothioacetamide. Methods: The reaction of 2-bromodimedone with cyanothioacetamide gave the 4,5,6,7-tetrahydrobenzo[d]- thiazol-2-yl derivative 4. The reactivity of compound 4 towards some chemical reagents was observed to produce different heterocyclic derivatives. Results: A cytotoxic screening was performed to evaluate the performance of the new derivatives in six tumor cell lines. Thirteen compounds were shown to be promising toward the tumor cell lines which were further evaluated toward five tyrosine kinases. Conclusion: The results of antitumor screening showed that many of the tested compounds were of high inhibition towards the tested cell lines. Compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 21b, 21c, 20d and 21d were the most potent compounds toward c-Met kinase and PC-3 cell line. The most promising compounds 6c, 8c, 11b, 11d, 13b, 14b, 15c, 15g, 20c, 20d, 21b, 21c and 21d were further investigated against tyrosine kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 6c, 11b, 11d, 14b, 15c, and 20d were selected to examine their Pim-1 kinase inhibition activity the results revealed that compounds 11b, 11d and 15c had high activities.

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Influence of chelidonine, an inhibitor of tubulin polymerisation on tyrosine kinase activity in normal, transformed and malignant cell lines

Biomedical Research ◽

10.2220/biomedres.25.27 ◽

2004 ◽

Vol 25 (1) ◽

pp. 27-33 ◽

Cited By ~ 2

Author(s):

Annie JOUBERT ◽

Mona-Liza LOTTERING ◽

Annie PANZER

Keyword(s):

Tyrosine Kinase ◽

Cell Lines ◽

Kinase Activity ◽

Malignant Cell ◽

Tyrosine Kinase Activity

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Pre-clinical evaluation of PV-10 for in vitro anti-tumor activity in refractory and high-risk adult solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14544 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14544-e14544

Author(s):

Son Tran ◽

Satbir Thakur ◽

Mohit Jain ◽

Chunfen Zhang ◽

Aru Narendran

Keyword(s):

High Risk ◽

Tumor Cell ◽

Solid Tumors ◽

Cell Lines ◽

Therapeutic Agent ◽

Intratumoral Injection ◽

Tumor Cell Lines ◽

Clinical Testing ◽

Anti Tumor Activity

e14544 Background: PV-10 (10% rose bengal disodium; 4,5,6,7-tetrachloro-2’,4’,5’,7’-tetraiodofluorescein) is a novel therapeutic agent previously shown to have potent anti-tumor activity following intratumoral injection in melanoma and refractory neuroblastoma, and currently is undergoing clinical testing as a single-agent for refractory metastatic neuroendocrine cancer (NCT02693067) and in combination with checkpoint inhibitors for metastatic melanoma (NCT02557321) and metastatic uveal melanoma (NCT00986661). Given the established clinical efficacy of PV-10 in adult melanoma and hepatic cancers via intratumoral injection, there is a need to evaluate the therapeutic potential of PV-10 in high-risk and refractory adult solid tumors via systemic administration. Our study aims to identify the clinical potential of systemically-delivered PV-10 by first generating prerequisite in vitro data for adult malignancies. Methods: Cytotoxicity assays were performed using the Alamar Blue assay to study the effects of PV-10 in vitro 96-hours post-treatment against a panel of adult solid tumor cell lines derived from breast (MCF-7, T-47D, MDA-MB-231), colorectal (HCT-116, LoVo, T-84), head and neck (CAL-27, Detroit-562, FaDu, UM-SCC-1), and testicular (NCC-IT, NTERA-2, TCAM-2) tissues. Light microscopy and Western blotting were used to investigate apoptosis induction and target modulation in tumor cells after PV-10 treatment. Results: In vitro results from our study demonstrate that PV-10 is cytotoxic at pharmacologically relevant concentrations across the indicated cell lines. Specifically, tumor cell lines originating from testicular tissues were highly sensitive to PV-10 treatment (Mean ± SD IC50: 37.5 ± 16.4 µM; n = 3) compared to breast (117.5 ± 71.0 µM; n = 3), colorectal (64.79 µM; n = 3), and head and neck (106.6 ± 29.2 µM; n = 4) cell lines. Western blot analyses showed dose- and time-dependent activation of pro-apoptotic protein markers in caspase-3 and PARP cleavage, indicating drug-induced apoptosis. Conclusions: This study provides the first pre-clinical results of PV-10 as a novel systemically-delivered therapeutic agent for a range of high-risk and refractory adult solid tumors. Data obtained from our in vitro experiments using a broad repertoire of cell lines that represent diverse molecular and phenotypic subtypes of solid tumors in adults can serve as prerequisite pre-clinical data to establish clinical testing in these populations.

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Enhancement of Growth of Human Colon Tumor Cell Lines by Feeder Layers of Murine Fibroblasts2

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/69.4.767 ◽

1982 ◽

Keyword(s):

Tumor Cell ◽

Cell Lines ◽

Human Colon ◽

Colon Tumor ◽

Tumor Cell Lines ◽

Murine Fibroblasts ◽

Feeder Layers ◽

Colon Tumor Cell

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Sensitivity of nuclear c-myc levels and induction to differentiation-inducing agents in human colon tumor cell lines

Cancer Letters ◽

10.1016/0304-3835(92)90179-y ◽

1992 ◽

Vol 62 (2) ◽

pp. 95-105 ◽

Cited By ~ 27

Author(s):

C.W. Taylor ◽

Y.S. Kim ◽

K.E. Childress-Fields ◽

L.C. Yeoman

Keyword(s):

Tumor Cell ◽

Cell Lines ◽

Human Colon ◽

Colon Tumor ◽

Tumor Cell Lines ◽

Colon Tumor Cell

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PKC412 Effectively Inhibits Constitutively Activated FGFR3 Mutants in Murine Leukemia Models and t(4;14) Myeloma Cell Lines.

Blood ◽

10.1182/blood.v104.11.2448.2448 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2448-2448

Author(s):

Jing Chen ◽

Benjamin H. Lee ◽

Ifor R. Williams ◽

Jeffery L. Kutok ◽

Nicole Duclos ◽

...

Keyword(s):

Multiple Myeloma ◽

Tyrosine Kinase ◽

Cell Lines ◽

Small Molecule ◽

Kinase Activity ◽

Cell Lymphoma ◽

Ectopic Expression ◽

B Cell Lymphoma ◽

Tyrosine Kinase Activity ◽

Significant Prolongation

Abstract Reccurent translocation t(4;14) associated ectopic expression of FGFR3, sometimes containing the activation mutation K650E (TDII), has been identified in 25% of human multiple myeloma (MM) patients and cell lines. However, current empirically-derived cytotoxic chemotherapy does not effectively treat this disease. One potential therapeutic strategy of treating MM is to inhibit the tyrosine kinase activity of FGFR3. In this report, we evaluated the efficacy of PKC412 (N-benzoyl-staurosporine), a small molecule tyrosine kinase inhibitor, for the treatment of FGFR3 mutants induced diseases. PKC412 effectively inhibits the tyrosine kinase activity and activation of downstream effector pathways of FGFR3 TDII or the constitutively activated TEL-FGFR3 fusion that was reported in a subtype of human peripheral T-cell lymphoma (PTCL), as well as proliferation of hematopoietic Ba/F3 cells transformed by the FGFR3 mutants. Furthermore, PKC412 drastically inhibits proliferation of four different multiple myeloma-derived primary cell lines that are associated with t(4;14) and expression of dysregulated FGFR3. Moreover, oral-gavage treatment with PKC412 resulted in statistically significant prolongation of survival in the murine bone marrow transplant (BMT) models of FGFR3 TDII-induced pre-B cell lymphoma or TEL-FGFR3 fusion-induced myeloproliferative disease, which suggests suitable pharmacokinetic and toxicity profiles of PKC412 for clinical use. Together, our data establish the small molecule inhibitor PKC412 as a molecularly targeted therapy for multiple myeloma and other human malignancies expressing activated FGFR3.

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Expression and secretion of VEGF in solid tumor cells is mediated by the mammalian target of rapamycin (mTOR)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14123 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14123-14123

Author(s):

E. M. Lackner ◽

M. T. Krauth ◽

R. Kondo ◽

L. Rebuzzi ◽

K. Eigenberger ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Cell ◽

Solid Tumors ◽

Tumor Cells ◽

Cell Lines ◽

Primary Tumor ◽

Tumor Cell Lines ◽

Neoplastic Cells ◽

Malignant Effusions ◽

Vegf Protein

14123 Background: Tumor progression and metastasis formation are often associated with enhanced angiogenesis and with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and a mediator of vascular permeability. We here describe that VEGF is produced and secreted by neoplastic cells in various solid tumors and its production mediated through mTOR. Methods and Results: As assessed by ELISA, the VEGF protein was detected in supernatants of cell lines derived from breast cancer (MDA-MB231), pancreatic carcinoma (BxPC-3), lung cancer (A-427), colon carcinoma (HCT8), and cholangiocellular carcinoma (EGI-1). In addition, VEGF was detected in supernatants of primary tumor cells obtained from malignant effusions in various malignancies (breast cancer, n=4; pancreatic cancer, n=1; ovarial cancer, n=1; parotic carcinoma, n=1; oesophageal carcinoma, n=1). In each case, VEGF protein was detectable in neoplastic cells by immunocytochemistry, and was found to accumulate in supernatants of cultured tumor cells over time, suggesting constant production and secretion. Correspondingly, as assessed by RT-PCR, primary tumor cells as well as the cell lines tested were found to express VEGF mRNA in a constitutive manner. Since mTOR is a well known regulator of VEGF synthesis, we applied rapamycin on primary neoplastic cells and on tumor cell lines. Rapamycin (20–200 nM) was found to counteract the production and secretion of VEGF in all tumor cells tested (VEGF in supernatants in cultures supplemented with rapamycin at 100 nM compared to control=100% on day 6: MDA-MB231: 11.8±0.2%; BxPC-3: 23.6±18.8%; A-427: 30.1±3.4%; HCT8 17.2±0.5%; EGI-1 28.4±1.1%; p<0.05). By contrast, neither rapamycin nor VEGF were found to modulate growth of primary tumor cells or the growth of the tumor cell lines tested. Conclusions: Various human tumor cells express and secrete VEGF. VEGF production is mediated through mTOR. These observations may have implications for the design of new treatment approaches attempting to counteract VEGF production/secretion and thus VEGF-dependent angiogenesis and effusion- formation in solid tumors. No significant financial relationships to disclose.

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