Abstract
We examined the effects of ALOS4, a cyclic peptide discovered previously by phage library selection against integrin αvβ3, on a human melanoma (A375) xenograft model to determine its abilities as a potential anti-cancer agent. We found that ALOS4 promoted healthy weight gain in A375-engrafted nude mice and reduced melanoma tumor mass and volume. Despite these positive changes, examination of the tumor tissue did not indicate any significant effects on proliferation, mitotic index, tissue vascularization, or reduction of αSMA or Ki-67 tumor markers. Modulation in overall expression of critical downstream αvβ3 integrin factors, such as FAK and Src, as well as reductions in gene expression of c-Fos and c-Jun transcription factors, indirectly confirmed our suspicions that ALOS4 is likely acting through an integrin-mediated pathway. Further, we found no overt formulation issues with ALOS4 regarding interaction with standard inert laboratory materials (polypropylene, borosilicate glass) or with pH and temperature stability under prolonged storage. Collectively, ALOS4 appears to be safe, chemically stable, and produces anti-cancer effects in a human xenograft model of melanoma. We believe these results suggest a role for ALOS4 in an integrin-mediated pathway in exerting its anti-cancer effects possibly through immune response modulation.
Highlights
Integrin αv β3 has been shown to play an essential role in different stages of cancer progression [1], metastasis [2], invasion [3,4], and angiogenesis [5]
The search for new therapeutic targets for a melanoma cure has revealed that overexpressed integrin αv β3 in transformed melanocytes [16] mediates tumor angiogenesis and is associated with organ-specific metastasis of human malignant melanoma [16], which has suggested a number of therapeutic approach possibilities for targeting αv β3
We have shown that ALOS4 treatment leads to tumor growth inhibition and increased survival of C57BL/6J mice inoculated with murine B16F10 melanoma cells
Summary
Integrin αv β3 has been shown to play an essential role in different stages of cancer progression [1], metastasis [2], invasion [3,4], and angiogenesis [5]. The search for new therapeutic targets for a melanoma cure has revealed that overexpressed integrin αv β3 in transformed melanocytes [16] mediates tumor angiogenesis and is associated with organ-specific metastasis of human malignant melanoma [16], which has suggested a number of therapeutic approach possibilities for targeting αv β3. Among the approaches [20] used to inhibit integrin signal transduction, tumor growth, angiogenesis, and metastasis are blocking αv β3 with monoclonal antibodies [21], cyclic RGD antagonist peptides [22], or other antagonists [8]. ALOS4, a synthetic 9-amino acid cyclic non-RGD peptide (NH2 -CSSAGSLFC-COOH (MW = 871.98)) was previously discovered using a phage–display technique targeted to integrin αv β3 binding [25,26]. Our findings suggest that ALOS4 is stable in chemical formulation and poses no overt toxicity risks, yet is effective in melanoma tumor reduction by an αv β3 -related mechanism and perhaps other mechanisms
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