In vitro- and in vivo-targeted tumor lysis by an MMP2 cleavable melittin-LAP fusion protein

Abstract

Abstract. Chemotherapy is one of the main treatment options for cancer, but the effectiveness of chemotherapeutic drugs is severely limited due to their systemic toxicity. Therefore, the need for a more targeted approach in tumor treatment is obvious. A tumor-activated agent would decrease systemic toxicity as well as increase the efficacy of the treatment. It has previously been shown that the latency of pro-TGF-ß is conferred by dimerization of two latency-associated peptides (LAP) that form a protective shield, which is cleaved off upon activation by matrix metalloproteinases (MMPs). It has also been shown that the fusion of this LAP peptide with other cytokines can confer their latency. In the present study, a recombinant adenovirus with a fusion gene encoding a tumor-activated pro-cytolytic peptide was made in which the LAP domain of TGF-ß was fused with melittin, a potent cytolytic toxin, with an MMP2 cleavage site in between the two. In vitro studies show that the melittin-MMP2-LAP recombinant adenovirus can be activated by MMP2 which leads to the release of free melittin to lyse the target cells. In vivo studies show approximately a 70% decrease in B16 tumor volume in melittin-MMP2-LAP recombinant adenovirustreated mice as compared to control mice. No significant systemic toxicity was observed in the treated mice.

Inhibition of telomerase activity by NME2: impact on metastasis suppression?

“…Consistent with this, Yu et al reported introduction of the full-length complementary DNA (cDNA) of human telomerase gene hTERT into a telomerase-negative osteosarcoma cell line U2OS (hTERT/U2OS) increased invasive ability of cells. As expected, telomere length in hTERT/U2OS cells was longer than that in vector control or un-transfected U2OS cells (Yu et al, 2009). …”

Melittin suppresses growth and induces apoptosis of non-small-cell lung cancer cells via down-regulation of TGF-β-mediated ERK signal pathway

“…Melittin was reported to be involved in apoptosis of human carcinoma cells by activating CaMKII-TAK1-JNK/p38 and inhibiting IkBa kinase-NF-kB pathways (14). Evidence indicates that melittin is a potent cytolytic toxin for tumor cells via in vitro-and in vivotargeted tumor lysis (15,16). In addition, melittin suppresses VEGF-A-induced tumor growth by blocking VEGFR-2 and the COX-2-mediated MAPK signaling pathway in lung cancer cells (17).…”

Apis melliferavenom induces different cell death pathways inTrypanosoma cruzi

“…It induces membrane permeabilization and lyses prokaryotic and eukaryotic cells in a non-selective manner (Papo and Shai, 2003). This mechanism of action is responsible for the haemolytic, anti-microbial (Blondelle and Houghten, 1991;Bechinger, 1997;Diaz-Achirica et al 1998;Chicharro et al 2001;Luque-Ortega et al 2003;Pérez-Cordero, 2011) andanti-tumour (Li et al 2006;Holle et al 2009) activities of melittin.…”

“…This mechanism of action is responsible for the haemolytic, anti-microbial (Blondelle and Houghten, 1991; Bechinger, 1997; Diaz-Achirica et al 1998; Chicharro et al 2001; Luque-Ortega et al . 2003; Pérez-Cordero, 2011) and anti-tumour (Li et al 2006; Holle et al 2009) activities of melittin.…”