Amblyomin-X induces ER stress, mitochondrial dysfunction, and caspase activation in human melanoma and pancreatic tumor cell

Morais, Katia L.P.; Pacheco, Mario Thiego Fernandes; Berra, Carolina Maria; Bosch, Rosemary Viola; Sciani, Juliana Mozer; Chammas, Roger; Saito, Renata de Freitas; Iqbal, Asif; Chudzinski-Tavassi, Ana Marisa

doi:10.1007/s11010-016-2683-4

Cited by 18 publications

(30 citation statements)

References 52 publications

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“…The prolongation of PT and aPTT is reversible [154]. Interestingly, several studies pointed out Amblyomin-X as an anti-cancer molecule in vitro and in vivo [154][155][156][157][158][159][160][161].…”

Section: Factor Xa Inhibitorsmentioning

confidence: 99%

Anticoagulants from Hematophagous

Chudzinski-Tavassi¹,

Faria²,

Flores³

2018

Anticoagulant Drugs

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This chapter will focus on anticoagulant molecules described until now from hematophagous animals. The evolutionary scenario for hematophagous animals is convergent and has resulted on a wide diversity of saliva anticoagulants, substances with platelet antiaggregation action, and also with vase-dilating action. Hematophagous animals such as bloodsuckers (leeches, mosquitoes, and ticks) have developed strategies that specifically target proteinases from the hemostatic system of the animals they feed, thus keeping the blood incoagulable. The saliva of those animals provides a large amount of molecules to modulate the innate immune response of the host and to inhibit blood coagulation in order to facilitate the feeding. Thus, anticoagulants from hematophagous animals represent a very interesting tool for studies ranging from basic research to applications in the therapeutic area, as anticoagulant medication. Several studies have pointed out that anticoagulants from hematophagous can also display non-hemostatic functions as antitumor, bringing new perspectives for the study of these molecules. The comprehension of the multi-faced physiological roles of those new anticoagulants from hematophagous opens new perspectives for therapeutic and biotechnological approaches.

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Section: Factor Xa Inhibitorsmentioning

confidence: 99%

Anticoagulants from Hematophagous

Chudzinski-Tavassi¹,

Faria²,

Flores³

2018

Anticoagulant Drugs

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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%

“…In previous studies, Amblyomin-X showed more avidity in the recognition of tumor cells, and rapid excretion in healthy murines 17 . We have already shown that Amblyomin-X causes cell death via induction of both endoplasmic reticulum (ER) stress and proteasome inhibition (PI) in renal adenocarcinoma (murine RENCA), in melanoma (murine B16F10 and human SK-MEL-28) 18 , as well as in pancreatic (human Mia-Paca-2) tumor cell lines 17,19,20 .…”

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confidence: 99%

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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“…In vitro incubation of plasma in the presence of amblyomin-X caused extended prothrombin time (PT) and aPTT. Amblyomin-X selectively induces apoptosis in tumor cells, and was able to promote a reduction in tumor size in a melanoma model; such antitumor activity, via induction of apoptosis and proteasome inhibition (Pacheco et al, 2014), may also be related to the regulation of host hemostasis Morais et al, 2016). In view of these interesting effects, the protein is being developed as an antitumor drug, and toxicity studies in animals are in progress (Maria et al, 2013;Drewes et al, 2012Drewes et al, , 2015Chudzinski-Tavassi et al, 2016).…”

Section: Roles Of Peptidase Inhibitors In the Tick−host Interfacementioning

confidence: 99%

Peptidase inhibitors in tick physiology

Parizi

Ali

Tirloni

et al. 2017

Medical Vet Entomology

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Abstract. Peptidase inhibitors regulate a wide range of physiological processes involved in the interaction between hematophagous parasites and their hosts, including tissue remodeling, the immune response and blood coagulation. In tick physiology, peptidase inhibitors have a crucial role in adaptation to improve parasitism mechanisms, facilitating blood feeding by interfering with defense-related host peptidases. Recently, a larger number of studies on this topic led to the description of several new tick inhibitors displaying interesting novel features, for example a role in pathogen transmission to the host. A comprehensive review discussing these emerging concepts can therefore shed light on peptidase inhibitor functions, their relevance to tick physiology and their potential applications. Here, we summarize and examine the general characteristics, functional diversity and action of tick peptidase inhibitors with known physiological roles in the tick−host−pathogen interaction.

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Amblyomin-X induces ER stress, mitochondrial dysfunction, and caspase activation in human melanoma and pancreatic tumor cell

Cited by 18 publications

References 52 publications

Anticoagulants from Hematophagous

Anticoagulants from Hematophagous

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

Peptidase inhibitors in tick physiology

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