ABSTRACT
Background: Mammary gland tumors are the most prevalent neoplasm in intact female dogs, and they are good natural models to study comparative oncology. Most canine mammary malignancies, as in women, are commonly refractory to conventional therapies and demand continuous new therapeutic approaches. Crotalus durissus terrificus, also called rattlesnake, has more than 60 different proteins in its venom with multiple pharmaceutical uses, such as antitumor, antiviral, and antimicrobial action. Crotoxin, a potent β-neurotoxin formed by the junction of two subunits, a basic subunit (CB-PLA2) and an acidic subunit (crotapotin), has already been reported to have anticancer properties in different types of cancers. Methods: In this work, we describe the cytotoxic potential of crotoxin and its subunits compared to doxorubicin (drug of choice) in two canine mammary carcinoma cell lines. Results: Crotoxin, CB-PLA2, crotalic venom, and doxorubicin decreased cell viability and the ability to migrate in a dose-dependent manner, and crotapotin did not present an antitumoral effect. For all compounds, the predominant cell death mechanism was apoptosis. In addition, crotoxin did not show toxicity in normal canine mammary gland cells. Conclusion: Therefore, this work showed that crotoxin and CB-PLA2 had cytotoxic activity, migration inhibition, and pro-apoptotic potential in canine mammary gland carcinoma cell lines, making their possible use in cancer research.
Subject(s)
Animals , Dogs , Mammary Neoplasms, Animal , Crotalus cascavella , Crotoxin , Cytotoxins , Dog Diseases , Elapid VenomsABSTRACT
The basic knowledge on neoplasms is increasing quickly; however, few advances have been achieved in clinical therapy against tumors. For this reason, the development of alternative drugs is relevant in the attempt to improve prognosis and to increase patients' survival. Snake venoms are natural sources of bioactive substances with therapeutic potential. The objective of this work was to identify and characterize the antitumoral effect of Crotalus durissus terrificus venom (CV) and its polypeptide, crotoxin, on benign and malignant tumors, respectively, pituitary adenoma and glioblastoma. The results demonstrated that CV possess a powerful antitumoral effect on benign (pituitary adenoma) and malignant (glioblastoma multiforme) tumors with IC50 values of 0.96 ± 0.11 µg/mL and 2.15 ± 0.2 µg/mL, respectively. This antitumoral effect is cell-cycle-specific and dependent on extracellular calcium, an important factor for crotoxin phospholipase A2 activity. The CV antitumoral effect can be ascribed, at least partially, to the polypeptide crotoxin that also induced brain tumor cell death. In spite of the known CV nephrotoxicity and neurotoxicity, acute treatment with its antitumoral dose established in vitro was not found to be toxic to the analyzed animals. These results indicate the biotechnological potential of CV as a source of pharmaceutical templates for cancer therapy.
Subject(s)
Animals , Male , Female , Rats , Adenoma , Crotalus cascavella , Neoplasms/therapy , Crotalid Venoms/therapeutic use , CrotoxinABSTRACT
Introdução - A atividade neurotóxica, miotóxica e coagulante do veneno das serpentes Crotalus durissus terrificus (VCdt) são responsáveis pelas altas taxas de mortalidade observada em acidentes envolvendo estas serpentes. Estes acidentes, quando ocorrem na gravidez, podem levar ao aborto devido à interferência com a homeostasia materna e/ou à embrioletalidade, por efeito direto do veneno. Materiais e Métodos - Este trabalho estudou os efeitos tóxicos do VCdt, administrado nas doses de 75 mg/kg ou 200 mg/kg por via subcutânea em camundongas no terceiro dia da sua gestação (período de pré-implantação). O grupo controle foi tratado da mesma forma que os experimentais, porém com solução salina. No último dia da gestação as fêmeas foram submetidas a eutanásia e observadas as possíveis malformações ósseas e viscerais de sua prole. Resultados e Conclusão - Os resultados mostraram que a administração da menor dose do VCdt não causou alterações significantes no desenvolvimento ósseo e visceral dos animais. No entanto, quando expostos a maior dose este promoveu aumento significante das anomalias e malformações, sugerindo que o envenenamento com esta dose no período inicial da gestação altera o desenvolvimento normal da prole de camundongos.
Introduction - The neurotoxic, myotoxic and coagulant activities of Crotalus durissus terrificus snake venom (VCdt) are responsible for the mortality rates observed in accidents involving the rattlesnake. Accidents during women pregnancy are a challenge, since animal venoms could led to pregnancy interruption as a consequence of maternal homeostasis disorder and/or a direct embryotoxic effect of the venom. Materials and Methods - In order to evaluate the possible embryotoxic effects of VCdt, doses of 75 mg/kg or 200 mg/kg of the venom were administered by subcutaneous route at day 3 of mice pregnancy (preimplantation period). The control group received saline in the same volume and during the same period as their respective experimental groups. The animals were submitted to euthanasia at term. Results and Conclusion - The treatment of the females during the preimplantation period did not cause significant changes in fetuses development, but the higher dose of the venom increased the number of anomalies or malformations of the fetuses.These results suggest that the VCdt in the higher dose (200 mg/kg) altered the normal development of the concept after implantation.