A synthetic peptide inhibitor for alpha-chemokines inhibits the tumour growth and pulmonary metastasis of human melanoma cells in nude mice.
Growth-related oncogene-alpha (GROalpha) was first described as an autocrine mitogen and growth factor for melanoma cells. More recent studies show that GROalpha, interleukin-8 (IL-8) and other members of the alpha-chemokine superfamily are also angiogenic. Therefore, we sought to determine if inhibitors of the alpha-chemokine receptor would be effective in inhibiting the tumour growth and pulmonary metastasis of human melanoma cells. We determined that melanocytes and 12 human melanoma cell lines produce both GROalpha and IL-8. The proliferation of A375SM, a highly metastatic cell line, and C8161-C were significantly increased by human recombinant GROalpha and inhibited by anti-human GROalpha monoclonal antibody. Antileukinate, a potent inhibitor of alpha-chemokine receptor binding, inhibited the binding of GROalpha to its receptors in melanocytes and all 12 melanoma cell lines tested. Antileukinate also suppressed proliferation of A375SM and C8161-C cells in a dose-dependent manner, and the suppression was not due to cytotoxic effects. Furthermore, continuous administration of antileukinate inhibited the tumour growth and pulmonary metastasis of A375SM cells in athymic BALB/c nude mice. These findings suggest that antileukinate inhibits the growth of melanoma cells by preventing GROalpha from binding to its receptors. This suggests a possible use of alpha-chemokine receptor inhibitors such as antileukinate in the treatment of malignant melanoma.
Fujisawa
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N
Department of Biochemistry, The University of Texas Health Center at Tyler, 75708-3154, USA.
Hayashi
S
S
Miller
E J
EJ
D000818:Animals; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors*; D002630:Chemotactic Factors / Q000032:analysis / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006133:Growth Substances / Q000032:analysis / Q000627:therapeutic use*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000032:analysis; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D008545:Melanoma / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010455:Peptides / Q000627:therapeutic use*; D013997:Time Factors; D014407:Tumor Cells, Cultured
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D010455:Peptides