Crotamine toxicity and efficacy in mouse models of melanoma

Pereira, Alexandre da Costa; Kerkis, Alexandre; Hayashi, Mirian A. F.; Pereira, Aparecida S. P.; Silva, Fernando S.; Oliveira, Eduardo B.; Silva, Álvaro Rossan de Brandão Prieto da; Yamane, Toshimi; Rádis-Baptista, Gandhi; Kerkis, Irina

doi:10.1517/13543784.2011.602064

Cited by 64 publications

(56 citation statements)

References 41 publications

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“…Previous studies have shown that naturally occurring CAPs such as the cell-penetrating peptide, crotamine, display potent cytotoxic activity against B16 melanoma cells in vitro as well as B16 melanomas established in syngeneic mice [38]. In the present study, the antitumor effect of LTX-315 against the highly aggressive and low immunogenic B16 melanoma cell line [39] was studied.…”

Section: Discussionmentioning

confidence: 96%

Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315

Camilio

Berge

Ravuri

et al. 2014

Cancer Immunol Immunother

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Malignant melanoma is the most aggressive and deadliest form of skin cancer due to its highly metastatic potential, which calls for new and improved therapies. Cationic antimicrobial peptides (CAPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line of defense against pathogens, and several CAPs have shown promising potential as novel anticancer agents. Structure–activity relationship studies on the CAP bovine lactoferricin allowed us to de novo design short chemically modified lytic anticancer peptides. In the present study, we investigated the in vivo antitumor effects of LTX-315 against intradermally established B16 melanomas in syngeneic mice. Intratumoral administration of LTX-315 resulted in tumor necrosis and the infiltration of immune cells into the tumor parenchyma followed by complete regression of the tumor in the majority of the animals. LTX-315 induced the release of danger-associated molecular pattern molecules such as the high mobility group box-1 protein in vitro and the subsequent upregulation of proinflammatory cytokines such as interleukin (IL) 1β, IL6 and IL18 in vivo. Animals cured by LTX-315 treatment were protected against a re-challenge with live B16 tumor cells both intradermally and intravenously. Together, our data indicate that intratumoral treatment with LTX-315 can provide local tumor control followed by protective immune responses and has potential as a new immunotherapeutic agent.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-014-1540-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 96%

Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315

Camilio

Berge

Ravuri

et al. 2014

Cancer Immunol Immunother

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“…Evidence indicates that K V channel activity is a critical regulator of tumor cell proliferation by membrane polarization (Wang et al, 2004;Pardo et al, 2005). Thus, if crotamine acts on K V 1.3 in nontoxic concentration to humans, it might also be involved with the previously reported efficacy as an antitumoral agent against several aggressive tumorigenic cell lineages, such as murine melanoma cells (B16-F10), human skin melanoma cells (SK-MEL-28), and pancreatic carcinoma cell line (MIA PaCa-2) (Pereira et al, 2011).…”

Section: Crotamine Pharmacology Revisited Through K V Channel Inhibitmentioning

confidence: 99%

Crotamine Pharmacology Revisited: Novel Insights Based on the Inhibition of K_V Channels

Peigneur¹,

Orts²,

Silva³

et al. 2012

Mol Pharmacol

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Crotamine, a 5-kDa peptide, possesses a unique biological versatility. Not only has its cell-penetrating activity become of clinical interest but, moreover, its potential selective antitumor activity is of great pharmacological importance. In the past, several studies have attempted to elucidate the exact molecular target responsible for the crotamine-induced skeletal muscle spasm. The aim of this study was to investigate whether crotamine affects voltagegated potassium (K V ) channels in an effort to explain its in vivo effects. Crotamine was studied on ion channel function using the two-electrode voltage clamp technique on 16 cloned ion channels (12 K V channels and 4 Na V channels), expressed in Xenopus laevis oocytes. Crotamine selectively inhibits K V 1.1, K V 1.2, and K V 1.3 channels with an IC 50 of ϳ300 nM, and the key amino acids responsible for this molecular interaction are suggested. Our results demonstrate for the first time that the symptoms, which are observed in the typical crotamine syndrome, may result from the inhibition of K V channels. The ability of crotamine to inhibit the potassium current through K V channels unravels it as the first snake peptide with the unique multifunctionality of cell-penetrating and antitumoral activity combined with K V channel-inhibiting properties. This new property of crotamine might explain some experimental observations and opens new perspectives on pharmacological uses.

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“…The toxin induces cell death in a dose-dependent manner in several actively proliferating cancer cells, but not in normal cells (Pereira et al, 2011). Crotamine cytotoxicity is related to the disruption of lysosomes and the activation of intracellular proteases (Hayashi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Soluble prokaryotic expression and purification of crotamine using an N-terminal maltose-binding protein tag

Jeong

et al. 2014

Toxicon

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Crotamine toxicity and efficacy in mouse models of melanoma

Abstract: These data warrant further exploration of crotamine as a tumor inhibition compound.

Cited by 64 publications

References 41 publications

Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315

Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315

Crotamine Pharmacology Revisited: Novel Insights Based on the Inhibition of K_V Channels

Soluble prokaryotic expression and purification of crotamine using an N-terminal maltose-binding protein tag

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Crotamine toxicity and efficacy in mouse models of melanoma

Abstract: These data warrant further exploration of crotamine as a tumor inhibition compound.

Cited by 64 publications

References 41 publications

Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315

Complete regression and systemic protective immune responses obtained in B16 melanomas after treatment with LTX-315

Crotamine Pharmacology Revisited: Novel Insights Based on the Inhibition of KV Channels

Soluble prokaryotic expression and purification of crotamine using an N-terminal maltose-binding protein tag

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Crotamine Pharmacology Revisited: Novel Insights Based on the Inhibition of K_V Channels