Disintegrins of Crotalus simus tzabcan venom: Isolation, characterization and evaluation of the cytotoxic and anti-adhesion activities of tzabcanin, a new RGD disintegrin

Saviola, Anthony J.; Modahl, Cassandra M.; Mackessy, Stephen P.

doi:10.1016/j.biochi.2015.07.005

Cited by 25 publications

(18 citation statements)

References 65 publications

(58 reference statements)

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“…Our results show that non-RGD disintegrin from C. d. colilineatus venom presents low cytotoxicity, although its toxicity increases with the concentration, having a dose-response effect. As in our results, the tzabcanin also showed dose-dependent toxicity against human malignant melanoma (A-357) and human colorectal adenocarcinoma (Colo-205) cell lines, but the viabilities of human breast adenocarcinoma (MCF-7) and human lung adenocarcinoma (A-549) cell lines were not affected [ 45 , 60 ]. Lebein inhibited the viability of human colon adenocarcinoma (HT29, LS174 and HCT116) and melanoma (SK-MEL-28 and LU-1205) cell lines [ 28 , 61 ].…”

Section: Discussionsupporting

confidence: 61%

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Cell migration inhibition activity of a non-RGD disintegrin from Crotalus durissus collilineatus venom

Oliveira

Manzini

Ferreira

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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BackgroundIn recent decades, snake venom disintegrins have received special attention due to their potential use in anticancer therapy. Disintegrins are small and cysteine-rich proteins present in snake venoms and can interact with specific integrins to inhibit their activities in cell-cell and cell-ECM interactions. These molecules, known to inhibit platelet aggregation, are also capable of interacting with certain cancer-related integrins, and may interfere in important processes involved in carcinogenesis. Therefore, disintegrin from Crotalus durissus collilineatus venom was isolated, structurally characterized and evaluated for its toxicity and ability to interfere with cell proliferation and migration in MDA-MB-231, a human breast cancer cell line.MethodsBased on previous studies, disintegrin was isolated by FPLC, through two chromatographic steps, both on reversed phase C-18 columns. The isolated disintegrin was structurally characterized by Tris-Tricine-SDS-PAGE, mass spectrometry and N-terminal sequencing. For the functional assays, MTT and wound-healing assays were performed in order to investigate cytotoxicity and effect on cell migration in vitro, respectively.ResultsDisintegrin presented a molecular mass of 7287.4 Da and its amino acid sequence shared similarity with the disintegrin domain of P-II metalloproteases. Using functional assays, the disintegrin showed low cytotoxicity (15% and 17%, at 3 and 6 μg/mL, respectively) after 24 h of incubation and in the wound-healing assay, the disintegrin (3 μg/mL) was able to significantly inhibit cell migration (24%, p < 0.05), compared to negative control.ConclusionThus, our results demonstrate that non-RGD disintegrin from C. d. collilineatus induces low cytotoxicity and inhibits migration of human breast cancer cells. Therefore, it may be a very useful molecular tool for understanding ECM-cell interaction cancer-related mechanisms involved in an important integrin family that highlights molecular aspects of tumorigenesis. Also, non-RGD disintegrin has potential to serve as an agent in anticancer therapy or adjuvant component combined with other anticancer drugs.

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Section: Discussionsupporting

confidence: 61%

“…Non-RGD disintegrin from C. d. collilineatus presents 7287.4 Da, as determined by MALDI-TOF, and it is similar to the molecular mass of others snake venom disintegrins, such as tzabcanin (7.1 kDa) [ 45 ], disintegrin from C. simus (7.1 kDa) [ 46 ] and proteomic data of C. d. collilineatus [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 78%

Cell migration inhibition activity of a non-RGD disintegrin from Crotalus durissus collilineatus venom

Oliveira

Manzini

Ferreira

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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“…Disintegrins are cysteine-rich peptides that result from the post-translational cleavage of snake venom metalloproteases (SVMPs), which are phylogenetically related with ADAMS (a disintegrin and metalloprotease). The possible function and activity of disintegrins in snake venoms is assigned to support the distribution of other toxins throughout prey tissues by binding integrins and inhibiting platelet aggregation direct upon envenomation [ 126 ]. Disintegrins are found in the venoms of mainly Crotalidae and Viperidae snakes, and constitute approximately 17% and 18% of total venom proteins, respectively [ 62 ].…”

Section: Snake Venom Peptides and Their Potential Pharmacological mentioning

confidence: 99%

Snake Venom Peptides: Tools of Biodiscovery

Munawar

Ali

Akrem

et al. 2018

Toxins

113

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Nature endowed snakes with a lethal secretion known as venom, which has been fine-tuned over millions of years of evolution. Snakes utilize venom to subdue their prey and to survive in their natural habitat. Venom is known to be a very poisonous mixture, consisting of a variety of molecules, such as carbohydrates, nucleosides, amino acids, lipids, proteins and peptides. Proteins and peptides are the major constituents of the dry weight of snake venoms and are of main interest for scientific investigations as well as for various pharmacological applications. Snake venoms contain enzymatic and non-enzymatic proteins and peptides, which are grouped into different families based on their structure and function. Members of a single family display significant similarities in their primary, secondary and tertiary structures, but in many cases have distinct pharmacological functions and different bioactivities. The functional specificity of peptides belonging to the same family can be attributed to subtle variations in their amino acid sequences. Currently, complementary tools and techniques are utilized to isolate and characterize the peptides, and study their potential applications as molecular probes, and possible templates for drug discovery and design investigations.

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“…A disintegrin isolated from the venom of the Middle American rattlesnake ( Crotalus simus tzabcan ) named tzabcanin [ 39 ], which has 71 amino acids and contains the canonical RGD-binding domain, exhibits a weak or null cytotoxic effect on cancer cell lines [ 39 ], but remarkable inhibitory effect of fibronectin- and vitronectin-dependent cell adhesion. This toxin binds αvβ3-integrins, which is the main receptor of the ECM protein vitronectin, inhibiting the adhesion and migration of melanoma and lung cancer cells [ 40 ].…”

Section: Inhibition Of Extracellular Matrix Component-dependent Admentioning

confidence: 99%

Targeting Metastasis with Snake Toxins: Molecular Mechanisms

Urra

Araya‐Maturana

2017

Toxins

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Metastasis involves the migration of cancer cells from a primary tumor to invade and establish secondary tumors in distant organs, and it is the main cause for cancer-related deaths. Currently, the conventional cytostatic drugs target the proliferation of malignant cells, being ineffective in metastatic disease. This highlights the need to find new anti-metastatic drugs. Toxins isolated from snake venoms are a natural source of potentially useful molecular scaffolds to obtain agents with anti-migratory and anti-invasive effects in cancer cells. While there is greater evidence concerning the mechanisms of cell death induction of several snake toxin classes on cancer cells; only a reduced number of toxin classes have been reported (i.e., disintegrins/disintegrin-like proteins, C-type lectin-like proteins, C-type lectins, serinproteases, cardiotoxins, snake venom cystatins) as inhibitors of adhesion, migration, and invasion of cancer cells. Here, we discuss the anti-metastatic mechanisms of snake toxins, distinguishing three targets, which involve (1) inhibition of extracellular matrix components-dependent adhesion and migration, (2) inhibition of epithelial-mesenchymal transition, and (3) inhibition of migration by alterations in the actin/cytoskeleton network.

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Disintegrins of Crotalus simus tzabcan venom: Isolation, characterization and evaluation of the cytotoxic and anti-adhesion activities of tzabcanin, a new RGD disintegrin

Cited by 25 publications

References 65 publications

Cell migration inhibition activity of a non-RGD disintegrin from Crotalus durissus collilineatus venom

Cell migration inhibition activity of a non-RGD disintegrin from Crotalus durissus collilineatus venom

Snake Venom Peptides: Tools of Biodiscovery

Targeting Metastasis with Snake Toxins: Molecular Mechanisms

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