title: Effects of antioxidants on drugs used against testicular cancer-induced alterations in metastasis-associated protein 1 signaling in the rat testis.
abstract: Metastasis-associated protein 1 (MTA1) is involved in tumor growth and metastasis of cancers. Being a component of nucleosome remodeling and histone deacetylase complex, the protein is also associated with DNA damage response pathway. Since the protein is involved in cancer pathology, we first investigated the effects of bleomycin, etoposide, and cisplatin (BEP) on MTA1 signaling in the testis. Second, since the antioxidants (AOs) have protective effects, we further investigated whether or not an AO cocktail modulates the effects of the drugs. Adult male Sprague Dawley rats (N = 4) were treated either with saline, or AO (α-tocopherol, l-ascorbic acid, zinc, and selenium), or therapeutic dose levels of etoposide (15 mg/kg) and cisplatin (3 mg/kg) from day 1-4 of the week and B (1.5 mg/kg) on the second day of the week, or BEP + AO. The real-time polymerase chain reaction showed that MTA1 and MTA1s (short form) gene expression was downregulated in AO (100% and 100%), BEP (86% and 71%), and BEP + AO (97% and 93%) groups. Western blotting and immunohistochemistry results showed that unnormalized MTA1 protein expression was upregulated in AO (38%) and BEP + AO (34%) groups; however, the MTA1/β-actin ratio was upregulated in all treated groups (21, 19, and 15%, respectively). In conclusion, the results indicate that both BEP and AO suppress MTA1 and MTA1s transcription, which may render the germ cells to be more prone to apoptosis. However, upregulation of MTA1 protein expression may be related to induced DNA damage. Modulation of MTA1 signaling is a novel mechanism of action of BEP and AO, which may be useful in developing newer anticancer drugs.
authors.affiliation: Department of Anatomy, Faculty of Medicine, Kuwait University, Safat, Kuwait knarayana@hsc.edu.kw.
authors.forename: Narayana
authors.initials: N
authors.lastname: Kilarkaje
authors.affiliation: Department of Physiology, Faculty of Medicine, Kuwait University, Safat, Kuwait.
authors.forename: Maie
authors.initials: M
authors.lastname: Al-Bader
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology; D001761:Bleomycin / Q000008:administration & dosage / Q000009:adverse effects; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D006655:Histone Deacetylases / Q000378:metabolism; D008297:Male; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012643:Selenium / Q000494:pharmacology; D015398:Signal Transduction; D013736:Testicular Neoplasms / Q000188:drug therapy*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D000975:Antioxidants; C121683:Mta1 protein, rat; D011506:Proteins; D001761:Bleomycin; D005047:Etoposide; D006655:Histone Deacetylases; D024502:alpha-Tocopherol; D012643:Selenium; D001205:Ascorbic Acid; D002945:Cisplatin
keywords: DNA damage repair; NuRD complex; apoptosis; cancer chemotherapy; cell cycle control; chromatin remodeling