Amblyomin-X, a recombinant Kunitz-type inhibitor, regulates cell adhesion and migration of human tumor cells

Schmidt, Mariana Costa Braga; Morais, Katia L.P.; Almeida, Maíra Estanislau Soares de; Iqbal, Asif; Goldfeder, Mauricio Barbugiani; Chudzinski-Tavassi, Ana Marisa

doi:10.1080/19336918.2018.1516982

Cited by 13 publications

(16 citation statements)

References 42 publications

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“…Amblyomin-X is a non-competitive inhibitor of FXa with a unique structure that acts on prothrombinase and tenase complexes. It was identified in the salivary glands of Amblyomma cajennense (currently A. sculptum ) [ 137 ] and was first described as an anti-coagulant [ 137 , 138 ] and later intensively investigated for its anti-tumor and anti-angiogenic effects [ 139 , 140 ]. Although the effects of Amblyomin-X on blood coagulation might be relevant to its antitumor effects, it has also been shown to have direct, non-hemostatic effects on cells such as proteasome and autophagy inhibition [ 134 ].…”

Section: Tick Salivary Glands: An Attractive Source Of Pis With Pomentioning

confidence: 99%

Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite–Host Crosstalk

Jmel

Aounallah

Bensaoud

et al. 2021

IJMS

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Protease inhibitors (PIs) are ubiquitous regulatory proteins present in all kingdoms. They play crucial tasks in controlling biological processes directed by proteases which, if not tightly regulated, can damage the host organism. PIs can be classified according to their targeted proteases or their mechanism of action. The functions of many PIs have now been characterized and are showing clinical relevance for the treatment of human diseases such as arthritis, hepatitis, cancer, AIDS, and cardiovascular diseases, amongst others. Other PIs have potential use in agriculture as insecticides, anti-fungal, and antibacterial agents. PIs from tick salivary glands are special due to their pharmacological properties and their high specificity, selectivity, and affinity to their target proteases at the tick–host interface. In this review, we discuss the structure and function of PIs in general and those PI superfamilies abundant in tick salivary glands to illustrate their possible practical applications. In doing so, we describe tick salivary PIs that are showing promise as drug candidates, highlighting the most promising ones tested in vivo and which are now progressing to preclinical and clinical trials.

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Section: Tick Salivary Glands: An Attractive Source Of Pis With Pomentioning

confidence: 99%

Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite–Host Crosstalk

Jmel

Aounallah

Bensaoud

et al. 2021

IJMS

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“…The list of proteins is shown in Table S9, including unique identifiers and the number of peptides. Interestingly, we found proteins related to biological effect previously reported in Amblyomin-X studies, such as apoptosis, mitochondrial dysfunction, regulation of cell migration and protein clearance, which includes cytochrome-c, plasminogen, actin cytoplasmic 1, fibronectin, heat shock protein HSP 90-alpha, E3 ubiquitin-protein ligase Mdm2, mitochondrial superoxide dismutase, and vimentin 15,18,42,43 . Furthermore, we identified immunogenic proteins such as Toll-like receptor 2 (TLR2) and T-cell surface antigen CD2 (CD2) as interacting partners of Amblyomin-X.…”

Section: Network Analyses With the Application Of String-db 93 Enrimentioning

confidence: 59%

Modulation of stress and immune response by Amblyomin-X results in tumor cell death in a horse melanoma model

Lichtenstein

Iqbal

Will

et al. 2020

Sci Rep

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We have investigated Amblyomin-X-treated horse melanomas to better understand its mode of action through transcriptome analysis and the in vivo model. Amblyomin-X is a Kunitz-type homologous protein that selectively leads to the death of tumor cells via ER stress and apoptosis, currently under investigation as a new drug candidate for cancer treatment. Melanomas are immunogenic tumors, and a better understanding of the immune responses is warranted. Equine melanomas are spontaneous and not so aggressive as human melanomas are, as this study shows that the in vivo treatment of encapsulated horse melanoma tumors led to a significant reduction in the tumor size or even the complete disappearance of the tumor mass through intratumoral injections of Amblyomin-X. Transcriptome analysis identified ER-and mitochondria-stress, modulation of the innate immune system, apoptosis, and possibly immunogenic cell death activation. Interactome analysis showed that Amblyomin-X potentially interacts with key elements found in transcriptomics. Taken together, Amblyomin-X modulated the tumor immune microenvironment in different ways, at least contributing to induce tumor cell death. Melanoma is a type of cancer arising from the malignant transformation of melanocytes, pigment producing-cells found predominantly in the basal layer of the epidermis and eyes. Cutaneous melanoma is the most aggressive and treatment-resistant form of skin cancer responsible for the vast majority of skin cancer-related deaths in the Caucasian population 1. The global incidence of melanoma continues to increase at an alarming rate, despite decades of public prevention programs in many countries. Around 232,000 new cases of skin cancer were recorded worldwide in 2012, accounting for 1.6% of all new cases of cancer back then, while over 300,000 new cases of melanoma were diagnosed worldwide in 2018, according to the World Cancer Research Foundation 2,3. In Brazil, 1,547 deaths were recorded in 2013 due to melanoma, with around 5,690 new cases reported back then, while around 6,260 new cases were expected due in 2018, according to the National Cancer Institute (INCA) 4. Cutaneous melanoma usually affects a higher proportion of patients, in the age range 40-60 years. They can be treated by surgical excision when detected in the early stage (0, I, II and resectable III), however, in the later stages (unresectable III, IV and recurrent melanoma) the treatment options are chemotherapy, target therapy (BRAF/ MEK pathway inhibitors), immunotherapy (checkpoint blockade CTLA-4 receptor inhibition, PD-1 ↔ PD-L1 axis inhibition, and interferon-gamma immunotherapy), or a combination of them. Death in most patients is caused by metastatic disease which may have evolved from the primary tumor. Therefore, there is a need for new

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“…Amblyomin-X, a Kunitz-type protease inhibitor, is profoundly exploited in pre-clinical testing and is under development for cancer treatment ( 26 ). It selectively induces apoptosis in tumor cells and promotes tumor reduction in vivo in melanoma animal models and reduce metastasis and tumor growth in in vivo experiments ( 56 ). In its pre-clinical evaluation, this protein was proven to significantly decrease lung metastasis in a mice orthotopic kidney tumor model ( 25 ).…”

Section: Impact Of Tick Salivary Compounds On Host Immune Responsesmentioning

confidence: 99%

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

et al. 2020

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Immunodeficiency disorders and autoimmune diseases are common, but a lack of effective targeted drugs and the side-effects of existing drugs have stimulated interest in finding therapeutic alternatives. Naturally derived substances are a recognized source of novel drugs, and tick saliva is increasingly recognized as a rich source of bioactive molecules with specific functions. Ticks use their saliva to overcome the innate and adaptive host immune systems. Their saliva is a rich cocktail of molecules including proteins, peptides, lipid derivatives, and recently discovered non-coding RNAs that inhibit or modulate vertebrate immune reactions. A number of tick saliva and/or salivary gland molecules have been characterized and shown to be promising candidates for drug development for vertebrate immune diseases. However, further validation of these molecules at the molecular, cellular, and organism levels is now required to progress lead candidates to clinical testing. In this paper, we review the data on the immunopharmacological aspects of tick salivary compounds characterized in vitro and/or in vivo and present recent findings on non-coding RNAs that might be exploitable as immunomodulatory therapies.

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Amblyomin-X, a recombinant Kunitz-type inhibitor, regulates cell adhesion and migration of human tumor cells

Cited by 13 publications

References 42 publications

Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite–Host Crosstalk

Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite–Host Crosstalk

Modulation of stress and immune response by Amblyomin-X results in tumor cell death in a horse melanoma model

Tick Salivary Compounds for Targeted Immunomodulatory Therapy

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