TIMP-1-GPI in combination with hyperthermic treatment of melanoma increases sensitivity to FAS-mediated apoptosis

• Published in: Cancer Immunology, Immunotherapy Vol. 58; no. 3; pp. 361 - 371
• Main Authors: Djafarzadeh, Roghieh, Milani, Valeria, Rieth, Nicole, von Luettichau, Irene, Skrablin, Petra S, Hofstetter, Monika, Noessner, Elfriede, Nelson, Peter J
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.03.2009; Springer-Verlag; Springer; Springer Nature B.V
• Subjects: Angiogenesis; Antineoplastic agents; Apoptosis; Biological and medical sciences; Biology; Cancer Research; Cancer therapies; Cell death; Cell growth; Cell Proliferation; Cell Separation; Cell Survival; Cloning; Dermatology; fas Receptor - metabolism; Flow Cytometry; Glycosylphosphatidylinositols - metabolism; Humans; Hyperthermia; Hyperthermia, Induced; Immunology; Immunotherapy; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Medical prognosis; Medical sciences; Medicine; Medicine & Public Health; Melanoma; Melanoma - therapy; Metastasis; Oncology; Original; Original Article; Pharmacology. Drug treatments; Proteins; Skin cancer; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Treatment Outcome; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Germany; TIMP-1-GPI; Hyperthermic therapy; Melanoma; Apoptosis; Drug combination; Tissue inhibitor metalloproteinase 1; Malignant tumor; Sensitivity; Treatment; Cell death; Immunotherapy; Malignant melanoma; Fas Antigen; Cancer
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-008-0559-5

Resistance to apoptosis is a prominent feature of malignant melanoma. Hyperthermic therapy can be an effective adjuvant treatment for some tumors including melanoma. We developed a fusion protein based on the tissue inhibitor of matrix metalloproteinase-1 linked to a glycosylphosphatidylinositol anchor (TIMP-1-GPI). The TIMP-1-GPI-fusion protein shows unique properties. Exogenous administration of TIMP-1-GPI can result in transient morphological changes to treated cells including modulation of proliferation and decreased resistance to apoptosis. The effect of TIMP-1-GPI on the biology of melanoma in the context of a defined hyperthermic dose was evaluated in vitro. Clonogenic assays were used to measure cell survival. Gelatinase zymography determined secretion of MMP-2 and MMP-9. Monoclonal antibody against FAS/CD95 was applied to induce apoptosis. The expression of pro- and anti-apoptotic proteins and the secretion of immunoregulatory cytokines were then evaluated using Western blot and ELISA. TIMP-1-GPI combined with a sub-lethal hyperthermic treatment (41.8°C for 2 h) suppressed tumor cell growth capacity as measured by clonogenic assay. The co-treatment also significantly suppressed tumor cell proliferation, enhanced FAS receptor surface expression increased tumor cell susceptibility to FAS-mediated killing. The increased sensitivity to FAS-induced apoptosis was linked to alterations in the apoptotic mediators Bcl-2, Bax, Bcl-XL and Apaf-1. The agent works in concert with sub-lethal hyperthermic treatment to render melanoma cells sensitive to FAS killing. The targeted delivery of TIMP-1-GPI to tumor environments in the context of regional hyperthermic therapy could be optimized through the use of thermosensitive liposomes.