RESUMO
Prostate cancer is the most highly diagnosed cancer in men worldwide. It is characterized by high proliferation, great invasion and metastatic potential. Sodium channel subtypes have been identified as highly expressed in different prostate cancer cell lines. In this study, we have screened the negatively charged fractions of Androctonus australis (Aa) scorpion venom to identify active peptides on DU145 prostate cancer cells proliferation. The most active compound was identified to be the sodium channel peptide AaHIV with an IC50 value of 15⯵M. At this concentration, AaHIV had low effect on the adhesion of DU145â¯cells to fibronectin. When compared to other Na+ channel Aa toxins, AaHIV was found to be 2 times more active than AaHI and AaHII on DU145â¯cells proliferation and slightly less active than AaHII on their adhesion. The three peptides are inactive on DU145â¯cells migration. AaHIV was found to be 16 times more active than veratridine, asteroidal alkaloid from plants of the lily family widely used as a sodium channel activator. Electrophysiological experiments showed that the AaHIV toxin activates Nav1.6 channel, suggesting that this sodium channel subtype is implicated in the proliferation of DU145 prostate cancer cells.
Assuntos
Neoplasias da Próstata/patologia , Venenos de Escorpião/farmacologia , Animais , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.6/efeitos dos fármacos , Canal de Sódio Disparado por Voltagem NAV1.6/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Escorpiões , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/metabolismoRESUMO
Scorpion toxins have been the subject of many studies exploring their pharmacological potential. The high affinity and the overall selectivity to various types of ionic channels endowed scorpion toxins with a potential therapeutic effect against many channelopathies. These are diseases in which ionic channels play an important role in their development. Cancer is considered as a channelopathy since overexpression of some ionic channels was highlighted in many tumor cells and was linked to the pathology progression. Interestingly, an increasing number of studies have shown that scorpion venoms and toxins can decrease cancer growth in vitro and in vivo. Furthermore through their ability to penetrate the cell plasma membrane, certain scorpion toxins are able to enhance the efficiency of some clinical chemotherapies. These observations back-up the applicability of scorpion toxins as potential cancer therapeutics. In this review, we focused on the anti-cancer activity of scorpion toxins and their effect on the multiple hallmarks of cancer. We also shed light on effectors and receptors involved in signaling pathways in response to scorpion toxins effect. Until now, the anticancer mechanisms described for scorpion peptides consist on targeting ion channels to (i) inhibit cell proliferation and metastasis; and (ii) induce cell cycle arrest and/or apoptosis through membrane depolarization leading to hemostasis deregulation and caspase activation. Putative targets such as metalloproteinases, integrins and/or growth factor receptors, beside ion channels, have been unveiled to be affected by scorpion peptides.