title: Nephrotoxicity of epigenetic inhibitors used for the treatment of cancer.
abstract: This study determined the anti-neoplastic activity and nephrotoxicity of epigenetic inhibitors in vitro. The therapeutic efficacy of epigenetic inhibitors was determined in human prostate cancer cells (PC-3 and LNCaP) using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-Aza) and the histone deacetylase inhibitor trichostatin A (TSA). Cells were also treated with carbamazepine (CBZ), an anti-convulsant with histone deacetylase inhibitor-like properties. 5-Aza, TSA or CBZ alone did not decrease MTT staining in PC-3 or LNCaP cells after 48 h. In contrast, docetaxel, a frontline chemotherapeutic induced concentration-dependent decreases in MTT staining. Pretreatment with 5-Aza or TSA increased docetaxel-induced cytotoxicity in LNCaP cells, but not PC-3 cells. TSA pretreatment also increased cisplatin-induced toxicity in LNCaP cells. Carfilzomib (CFZ), a protease inhibitor approved for the treatment of multiple myeloma had minimal effect on LNCaP cell viability, but reduced MTT staining 50% in PC-3 cells compared to control, and pretreatment with 5-Aza further enhanced toxicity. Treatment of normal rat kidney (NRK) and human embryonic kidney 293 (HEK293) cells with the same concentrations of epigenetic inhibitors used in prostate cancer cells significantly decreased MTT staining in all cell lines after 48 h. Interestingly, we found that the toxicity of epigenetic inhibitors to kidney cells was dependent on both the compound and the stage of cell growth. The effect of 5-Aza and TSA on DNA methyltransferase and histone deacetylase activity, respectively, was confirmed by assessing the methylation and acetylation of the CDK inhibitor p21. Collectively, these data show that combinatorial treatment with epigenetic inhibitors alters the efficacy of chemotherapeutics in cancer cells in a compound- and cell-specific manner; however, this treatment also has the potential to induce nephrotoxic cell injury.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Scholpa
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Kolli
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA.
authors.forename: M
authors.initials: M
authors.lastname: Moore
authors.affiliation: Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Arnold
authors.affiliation: Department of Environmental Health Science, University of Georgia, Athens, GA 30602, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Glenn
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA. Electronic address: bsc@rx.uga.edu.
authors.forename: B S
authors.initials: BS
authors.lastname: Cummings
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use*; D001374:Azacitidine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D000077143:Docetaxel; D044127:Epigenesis, Genetic / Q000187:drug effects*; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008745:Methylation / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009842:Oligopeptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000235:genetics; D051381:Rats; D043823:Taxoids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D006877:Hydroxamic Acids; D009842:Oligopeptides; D043823:Taxoids; D000077143:Docetaxel; C012589:trichostatin A; C524865:carfilzomib; D001374:Azacitidine; D002945:Cisplatin
keywords: Epigenetic inhibitors; Kidney cells; Nephrotoxicity; Prostate cancer