Antiproliferative effects of masitinib and imatinib against canine oral fibrosarcoma in vitro

Milovancev, Milan; Helfand, Stuart C.; Marley, Kevin; Goodall, Cheri P.; Löhr, Christiane V.; Bracha, Shay

doi:10.1186/s12917-016-0712-x

Cited by 14 publications

(16 citation statements)

References 42 publications

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“…Masitinib induced a dose-dependent inhibition of cell growth in both CMT cell lines, and these results suggest that CMT cells are sensitive to masitinib and that it is an effective agent for suppressing the growth of CMT cells in vitro. In the present study, the calculated IC50 values of masitinib are similar to the nM to low µM-ranging IC50 values of masitinib found in various cancer cell lines treated with the preparation (6,15,18). The reported IC50 values of masitinib for canine oral fibrosarcoma cell lines were 9.1 and 12.0 μM (18) and for canine haemangiosarcoma cell lines were 8.56, 9.41 and 10.65 μM (15).…”

Section: Discussionsupporting

confidence: 86%

“…It has demonstrated good clinical efficacy in unresectable mast cell tumours in dogs and is under clinical assessment as a therapeutic agent in several human cancers which involve c-Kit proto-oncogene mutations similar to those in canine neoplasms (16,21). The promising clinical efficiency of masitinib in c-Kit-positive mast cell tumours has encouraged preclinical studies and clinical evaluations of masitinib in many other canine malignancies (6,8,18). The c-Kit proto-oncogene is reported to be frequently expressed in canine malignant mammary tumours (13).…”

Section: Discussionmentioning

confidence: 99%

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Effects of tyrosine kinase inhibitor-masitinib mesylate on canine mammary tumour cell lines

Alkan¹,

Bakırel²,

Üstüner³

et al. 2021

Journal of Veterinary Research

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Introduction Masitinib mesylate, a selective tyrosine kinase inhibitor of the c-KIT receptor, is used for the treatment of mast cell tumours in dogs. Masitinib has previously been investigated in various cancers; however, its potential anticancer effect in canine mammary tumours (CMTs) is unknown. In the present paper, we investigated the antiproliferative effect of masitinib in CMT cells and its possible mechanisms of action. Material and Methods The effect of masitinib on the proliferation of CMT-U27 and CMT-U309 cells was assessed by MTT assay and DNA fragmentation. Flow cytometric analysis was used to measure the effect of masitinib on apoptosis and the cell cycle. Additionally, vascular endothelial growth factor levels (VEGF) were measured, and the proliferation marker Ki-67 was visualised in immunocytochemical stainings in CMT cells. Results Treatment with masitinib inhibited the proliferation of CMT cells in a concentration-dependent manner. Maximal apoptotic activity and DNA fragmentation were observed at approximately IC50 of masitinib in both cell lines. In addition, cell cycle distribution was altered and VEGF levels and Ki-67 proliferation indices were decreased in masitinib-treated cells in comparison with control cells. Conclusion In this study, masitinib suppressed cell proliferation concomitantly via induction of apoptosis and cell cycle arrest by decreasing VEGF levels and the Ki-67 proliferation index in CMT-U27 and CMT-U309 cells in vitro, suggesting its potential as a therapeutic tool in the clinical setting of mammary cancer treatment in dogs.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Effects of tyrosine kinase inhibitor-masitinib mesylate on canine mammary tumour cell lines

Alkan¹,

Bakırel²,

Üstüner³

et al. 2021

Journal of Veterinary Research

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“…Considering the results we obtained as a whole, it is conceivable to hypothesize that the mild inhibition observed in canine KIT mRNA and protein after exposure to AQ1 might not univocally derive from the interaction between the ligand and the G4 in the promoter. Rather, it might be a consequence of other molecular mechanisms related to the cellular response to anticancer drugs such as TKIs and doxorubicin (van de Ven et al, 2011;Yamada et al, 2011;Rossi et al, 2013;Milovancev et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Targeting Canine KIT Promoter by Candidate DNA G-Quadruplex Ligands

Zorzan

Ros

Giantin

et al. 2018

The Journal of Pharmacology and Experimental Therapeutics

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G-quadruplexes (G4) are nucleic acid secondary structures frequently assumed by G-rich sequences located mostly at telomeres and proto-oncogenes promoters. Recently, we identified, in canine KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) promoter, two G-rich sequences able to fold into G4: d_kit1 and d_kit2_A16. In this study, an anthraquinone (AQ1) and an anthracene derivative (AN6), known to stabilize the G4 structures of the corresponding human h_kit1 and h_kit2, were tested on the canine G4 and in two canine mast cell tumor (MCT) cell lines (C2 and NI-1) to verify their capability to down-regulate KIT expression. The cytotoxicity of AQ1 and AN6 was determined using the Alamar Blue test; also the constitutive expression of KIT and other proto-oncogenes containing G4 structures in their promoter (BCL2, VEGFa, VEGFR2, KRAS, and TERT) was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Then the time-and dose-dependent effects of both ligands on target gene expression were assessed by qRT-PCR. All target genes were constitutively expressed up to 96 hours of culture. Both ligands decreased KIT mRNA levels and c-kit protein amount, and AN6 was comparatively fairly more effective. DNA interaction studies and a dualluciferase gene reporter assay performed on a noncancerous canine cell line (Madin-Darby Canine Kidney cells) proved that this down-regulation was the result of the interaction of AN6 with KIT proximal promoter. Interestingly, our results only partially overlap with those previously obtained in human cell lines, where AQ1 was found as the most effective compound. These preliminary data might suggest AN6 as a promising candidate for the selective targeting of canine KIT-dependent tumors.

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“…Most of the Pt release occurred within the first week in this study, with mean peak Pt concentrations diffusing to a radial distance of 2 cm by day 7 and to all distances at low concentrations for up to 21 days. Although Pt was detectable in tissues at day 21, concentrations at that time were below cytotoxic concentrations reported in vitro for canine and feline cancer cells . Spacing closer than 2 cm may be required to maintain cytotoxic concentrations of Pt in the tumor bed.…”

Section: Discussionmentioning

confidence: 75%

Pharmacokinetics of platinum and safety evaluation of carboplatin‐impregnated calcium sulfate hemihydrate beads after implantation in healthy cats

et al. 2020

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Objective: To evaluate the pharmacokinetics (PK) of platinum (Pt) and safety of carboplatin-impregnated calcium sulfate hemihydrate (C-I CSH) beads after implantation in healthy cats. Study design:In vivo experimental study. Animals: Six healthy adult cats.Methods: Three C-I CSH beads were implanted in muscle pockets over the right and left hemithoraces of each cat (~3.9 mg/kg of Pt; 60.4 mg/m 2 of calculated carboplatin). Hematology and blood chemistry were tested at baseline and 3, 7, 14, and 21 days postimplantation. Serum was analyzed for Pt at specific times from 1 hour to 21 days. Tissue was obtained for histopathology and analysis of Pt at 3, 7, 14, and 21 days at standardized distances from implantation sites.Results: Platinum was detected in tissues at all times and distances (range, 0.1-4.19 μg/g). Serum Pt increased up to 2.6 hours (3.25 μg/mL) then decreased sharply. Samples containing muscle had higher Pt compared with samples without muscle (P = .004). Mild hypercalcemia was noted in four cats, and mild inflammatory reaction was noted on histopathology of all samples.Results of this study were presented in part at

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Antiproliferative effects of masitinib and imatinib against canine oral fibrosarcoma in vitro

Cited by 14 publications

References 42 publications

Effects of tyrosine kinase inhibitor-masitinib mesylate on canine mammary tumour cell lines

Effects of tyrosine kinase inhibitor-masitinib mesylate on canine mammary tumour cell lines

Targeting Canine KIT Promoter by Candidate DNA G-Quadruplex Ligands

Pharmacokinetics of platinum and safety evaluation of carboplatin‐impregnated calcium sulfate hemihydrate beads after implantation in healthy cats

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