Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

Bocci, Guido; Fioravanti, Anna; Motta, Concettina La; Orlandi, Paola; Canu, Bastianina; Desidero, Teresa Di; Mugnaini, Laura; Sartini, Stefania; Cosconati, Sandro; Frati, Rita; Antonelli, Alessandro; Berti, Piero; Miccoli, Paolo; Settimo, Federico Da; Danesi, Romano

doi:10.1016/j.bcp.2011.03.022

Cited by 26 publications

(20 citation statements)

References 49 publications

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“…Interestingly, in the primary DePTC cells the anti-proliferative action of CLM3 and CLM29 observed was independent from the presence or absence of RET/PTC or BRAF mutation. These results concur well with the concept that CLM3 and CLM29 are proposed for a multiple signal transduction inhibition (including the RET, TK, EGFR, VEGFR) and they have an anti-angiogenic effect [50, 51]. …”

Section: Targeted Therapy For Thyroid Cancersupporting

confidence: 88%

Personalization of Targeted Therapy in Advanced Thyroid Cancer

Fallahi

Ferrari

Mazzi

et al. 2014

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Although generally the prognosis of differentiated thyroid carcinoma (DTC) is good, approximately 5% of people are likely to develop metastases which fail to respond to radioactive iodine, and other traditional therapies, exhibiting a more aggressive behavior. Nowadays, therapy is chosen and implemented on a watch-and-wait basis for most DTC patients. Which regimen is likely to work best is decided on the basis of an individual’s clinical information, but only data referring to outcomes of groups of patients are employed. To predict the best course of therapy, an individual patient’s biologic data is rarely employed in a systematic way. Anyway, the use of not expensive individual genomic analysis could lead us to a new era of patient-specific and personalized care. Recently, key targets that are now being evaluated in the clinical setting have been evidenced in the pathogenesis of these diseases. Some of the known genetic alterations playing a crucial role in the development of thyroid cancer include B-Raf gene mutations, rearranged during transfection/ papillary thyroid carcinoma gene rearrangements, and vascular endothelial growth factor receptor-2 angiogenesis pathways. The development of targeted novel compounds able to induce clinical responses and stabilization of disease has overcome the lack of effective therapies for DTC, which are resistant to radioiodine and thyroid stimulating hormone-suppressive therapy. Interestingly, the best responses have been demonstrated in patients treated with anti-angiogenic inhibitors such as vandetanib and XL184 in medullary thyroid cancer, and sorafenib in papillary and follicular DTC.

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Section: Targeted Therapy For Thyroid Cancersupporting

confidence: 88%

Personalization of Targeted Therapy in Advanced Thyroid Cancer

Fallahi

Ferrari

Mazzi

et al. 2014

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“…ATC cells (5x10 4 cells/well) were plated in 1% FBS medium for 24 h, and then treated for 72 h with vandetanib at a concentration similar to the experimental IC 50 of cell proliferation (25 µM for ATC), and with a higher (50 µM), or with a lower (1 µM) concentration of vandetanib, or with vehicle. We collected cell lysates as previously reported (25) and we assayed them with PathScan phospo-EGFR (Tyr1173) and total EGFR sandwich ELISA kits (Cell Signaling Technology, Inc., Danvers, MA, USA). Optical density (OD) was estimated at 450 nm.…”

Section: Elisa Tests In Atc Cellsmentioning

confidence: 99%

“…AKT (pThr308), or ERK1/2 (pTpY185/187). ATC cells (5x10 4 cells/well) were exposed for 72 h to vandetanib and subsequently lysed (25), and tested for human AKT or ERK1/2 phosphorylation by the PhosphoDetect AKT (pThr308) or by PhosphoDetect ERK1/2 (pThr185/pTyr187) ELISA kits (Calbiochem; EMD Millipore, Billerica, MA, USA). Data were normalized by total protein AKT, or ERK1/2 concentrations evaluated by AKT, or ERK1/2 ELISA kits, respectively.…”

Section: Elisa Tests In Atc Cellsmentioning

confidence: 99%

Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo

et al. 2018

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The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATC‑cell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 µM) was tested by WST‑1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dose‑dependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30 days. Vandetanib (25 mg/kg/day) significantly inhibited tumor growth and VEGF‑A expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation.

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“…Although trusting both in the already available compounds and in the numerous forthcoming protein kinase inhibitors currently under investigation, we can easily assert that a great deal still has to be done in the area of TCs treatment, in order to provide a safe, effective, and long lasting therapeutic protocol to the steadily increasing population affected by these malignancies.…”

Section: Current Therapies In Thyroid Carcinomasmentioning

confidence: 99%

“…Acquired resistance to initially active kinase inhibitors may also emerge, as a consequence of prolonged administration, and this issue further circumscribes the plain exploitability of these compounds as effective agents against TCs. 82 Although trusting both in the already available compounds and in the numerous forthcoming protein kinase inhibitors currently under investigation, [83][84][85][86][87][88][89][90] we can easily assert that a great deal still has to be done in the area of TCs treatment, in order to provide a safe, effective, and long lasting therapeutic protocol to the steadily increasing population affected by these malignancies.…”

Section: F I G U R E 5 Tyrosine Kinase Inhibitors Under Clinical Invementioning

confidence: 99%

Novel therapeutic clues in thyroid carcinomas: The role of targeting cancer stem cells

Antonelli

Motta

2017

Medicinal Research Reviews

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Thyroid carcinomas (TCs), the most common endocrine tumors, represent the eighth most common cancer diagnosed worldwide in both women and men. To treat these malignancies, several drugs are now available and a number of novel ones have been enrolling in clinical trials, addressing both oncogenic pathways in cancer cells and angiogenic pathways in tumor endothelial cells. However, their use is not devoid of serious toxicities and their efficacy is limited, being dependent on carcinoma typology and the occurrence of acquired resistance. Accordingly, it is time to recast therapeutic strategies against these types of tumors to get to newer and fully effective drugs. In this perspective, latest findings demonstrate that cancer stem cells (CSCs) represent a challenging target to strike. They possess core traits of self-renewal and differentiation, being resistant to the effects of chemotherapy and radiation and playing a key role in mediating metastasis. Therefore, basic molecular elements sustaining both development of thyroid cancer stem cells and their residence in the stemness condition represent a set of innovative and still unexplored targets to address. In this review, a thorough literature survey has been accomplished, to take stock of mechanisms governing thyroid carcinomas and to point out both their currently available treatments and the novel forthcoming ones. Pubmed, Scifinder and ClinicalTrials.gov were exploited as research applications and registry database, respectively. Original articles, reviews, and editorials published within the last ten years, as well as open clinical investigations in the field, were analyzed to suggest new exciting therapeutic opportunities for people affected by TCs.

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Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

Cited by 26 publications

References 49 publications

Personalization of Targeted Therapy in Advanced Thyroid Cancer

Personalization of Targeted Therapy in Advanced Thyroid Cancer

Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo

Novel therapeutic clues in thyroid carcinomas: The role of targeting cancer stem cells

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