, 1997), BV is a very complex mixture of components that may cause other physiological effects. The first study was published by Havas in 1950 and, after 30 years, other groups started to carry on interesting studies about the cytotoxicity Ibrutinib mw of bee venom upon tumor cells. Due to the promising effects found, publications have been constantly growing, showing not only the effects of BV in tumor cell lines, but also characterizing the signaling pathways through which the venom inhibits cellular proliferation, besides many interesting in vivo studies. BV is known for being composed of a complex mixture of
active peptides, enzymes and amines (Dotimas and Hider, 1987 and Habermann, 1972). Besides melittin and PLA2, other important components are histamines, catecholamines and polyamines. Melittin is by far the peptide CYC202 manufacturer with the greatest anti-tumor activity isolated from BV, acting in different ways upon the physiology of cancer cells. Melittin is a small and amphiphilic peptide
containing 26 amino acid residues and is the principal toxin derived from the venom of the bee, Apis mellifera. The sequence of melittin is Gly-Ile-Gly-Ala-Val-Leu-Lys-Val-Leu-Thr-Thr-Gly-Leu-Pro-Ala-Leu-Ile-Ser-Trp-Ile-Lys-Arg-Lys-Arg-Gln-Gln ( Gevod and Birdi, 1984). Melittin exhibits anti-microbial activities and pro-inflammatory effects ( Sumikura et al., 2003), besides inducing perturbations in the cell membrane and damage to enzyme systems ( Habermann, 1972 and Wade et al., 1990). Several cancer cells, including leukemia, renal, lung, liver, prostate, bladder, and mammary cancer cells, can be targets of melittin ( Son et al., 2007). Chueng (1982) has shown that melittin is capable of binding calmodulin,
D-malate dehydrogenase which has a role in cellular proliferation. Hait et al. (1983) also showed that melittin is one of the most powerful inhibitors of calmodulin activity and, as such, is an inhibitor of cell growth and clonogenicity of human and murine leukemic cells ( Hait et al., 1983, Hait et al., 1985 and Lee and Hait, 1985). Gest and Salomon (1987) showed that melittin inhibits the melanotropin receptor in M2R melanoma cell membranes. Other studies suggest that melittin acts in the same manner as pore-forming agents, killing malignant cells ( Duke et al., 1994 and Shaposhnikova et al., 1997). Most recent studies have shown that melittin kills tumor cells by apoptosis through several cancer cell death mechanisms, including the activation of caspase and matrix metalloproteinases (MMP) ( Holle et al., 2003 and Moon et al., 2006). Besides the above-mentioned effects, melittin also leads to cell death by other means. Sharma (1992) showed that melittin preferentially hyperactivates PLA2 in ras oncogene-transformed cells, resulting in their selective destruction.