title: Thalidomide combined with irradiation alters the activity of two proteases.
abstract: The aim of the present study was to investigate the effects of thalidomide, a drug known for its anti‑angiogenic and antitumor properties, at its cytotoxic dose previously determined as 40 µg/ml (according to four cytotoxic test results). The effect of the drug alone and in combination with radiotherapy using Cobalt 60 (60Co) at 45 Gy on the enzymatic activity of substance‑P degrading A disintegrin and metalloproteinase (ADAM)10 and neprilysin (NEP) was investigated in the mouse breast cancer cell lines 4T1 and 4T1 heart metastases post‑capsaicin (4THMpc). Thalidomide (40 µg/ml) exerted differing effects on the activities of ADAM10 and NEP enzymes. In 4T1 cells, 40 µg/ml thalidomide alone did not alter ADAM10 enzyme activity. 60Co irradiation at 45 Gy alone caused a 42% inhibition in ADAM10 activity, however, the inhibition increased to 89% when combined therapy was used. By contrast, in the 4THMpc cell line, 40 µg/ml thalidomide alone induced a 66.6% increase in ADAM10 enzyme activity. Radiotherapy alone and thalidomide with 60Co combined therapy caused a 33.3 and 40% inhibition of ADAM10 activity, respectively. In 4T1 cells, thalidomide alone caused a 40.9% increase in NEP activity. Radiation therapy alone or in combination with the drug caused a 40.7% increase in NEP activity. In more aggressive 4THMpc cells, thalidomide alone caused a 26.6% increase in NEP activity. Radiotherapy alone and combined therapy caused a 33.3 and 37% increase in enzyme activity, respectively. To the best of our knowledge, the present study is the first to demonstrate that thalidomide alone or in combination with radiotherapy exhibits significant cytotoxic effects on 4T1 and 4THMpc mouse breast cancer cell lines indicating that this drug affects the enzymatic activity of ADAM10 and NEP in vitro.
authors.affiliation: Department of Nutrition and Dietetics, Akdeniz University, Antalya School of Health, Antalya 07058, Turkey.
authors.forename: Ece
authors.initials: E
authors.lastname: Şimşek
authors.affiliation: Department of Biology, Akdeniz University, Science Faculty, Antalya 07058, Turkey.
authors.forename: Esra
authors.initials: E
authors.lastname: Aydemir
authors.affiliation: Department of Radiation Oncology, Akdeniz University, Medicine Faculty, Antalya 07058, Turkey.
authors.forename: Aylin Fidan
authors.initials: AF
authors.lastname: Korcum
authors.affiliation: Department of Biology, Akdeniz University, Science Faculty, Antalya 07058, Turkey.
authors.forename: Kayahan
authors.initials: K
authors.lastname: Fişkın
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D003037:Cobalt Radioisotopes / Q000737:chemistry; D005260:Female; D005720:Gamma Rays; D006338:Heart Neoplasms / Q000473:pathology / Q000556:secondary; D007166:Immunosuppressive Agents / Q000633:toxicity*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D015260:Neprilysin / Q000378:metabolism*; D013792:Thalidomide / Q000633:toxicity*
chemical_list: D003037:Cobalt Radioisotopes; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D013792:Thalidomide; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D015260:Neprilysin; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse