Abstract
The increased incidence, high rates of mortality and few effective means of treatment of malignant melanoma, stimulate the search for new anti-tumor agents and therapeutic targets to control this deadly metastatic disease. In the present work the antitumor effect of arazyme, a natural bacterial-derived metalloprotease secreted by Serratia proteomaculans, was investigated. Arazyme significantly reduced the number of pulmonary metastatic nodules after intravenous inoculation of B16F10 melanoma cells in syngeneic mice. In vitro, the enzyme showed a dose-dependent cytostatic effect in human and murine tumor cells, and this effect was associated to the proteolytic activity of arazyme, reducing the CD44 expression at the cell surface, and also reducing in vitro adhesion and in vitro/in vivo invasion of these cells. Arazyme treatment or immunization induced the production of protease-specific IgG that cross-reacted with melanoma MMP-8. In vitro, this antibody was cytotoxic to tumor cells, an effect increased by complement. In vivo, arazyme-specific IgG inhibited melanoma lung metastasis. We suggest that the antitumor activity of arazyme in a preclinical model may be due to a direct cytostatic activity of the protease in combination with the elicited anti-protease antibody, which cross-reacts with MMP-8 produced by tumor cells. Our results show that the bacterial metalloprotease arazyme is a promising novel antitumor chemotherapeutic agent.
Highlights
Melanoma is a fatal skin cancer, with increased incidence in recent years [1,2]
In the present work we show that arazyme has a potent inhibitory effect on metastatic melanoma B16F10 preclinical model in vivo
Bacterial Arazyme Inhibits Metastatic Melanoma group showed around 200 pulmonary nodules, all animals in the treated group showed less than 20 nodules
Summary
Despite improvements in awareness and early detection, the mortality in patients with melanoma is still quite high [3]. A median survival of 8–18 months after diagnosis of metastatic melanoma has been observed [4]. Until 2011, only dacarbazine and high-dosage of interleukin-2 had been approved for melanoma treatment by the Food and Drug Administration (FDA), with durable responses in some patients with metastatic disease [5,6]. The newly approved therapies, ipilimumab (anti-CTLA-4 antibody) and vemurafenib (B-RAFV600E kinase inhibitor), have shown a survival benefit in large randomized clinical trials, but still with low frequency of objective results [7,8]. Chemotherapy used against metastatic melanoma often generates a large number of adverse side effects, leading to interruption of the treatment [9]
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