Ubiquitous induction of resistance to platinum drugs in human ovarian, cervical, germ-cell and lung carcinoma tumor cells overexpressing isoforms 1 and 2 of dihydrodiol dehydrogenase.
We have recently demonstrated that overexpression of dihydrodiol dehydrogenase (DDH) in human ovarian carcinoma cells (2008/C13*) is associated with cisplatin and carboplatin resistance. Furthermore, we have also elucidated that transfection of parental human ovarian carcinoma cells with a full-length DDH1 cDNA leads to induction of resistance to the platinum drugs. The development of cisplatin resistance in the transfected cells is associated with an increase in DDH enzyme activity. Previous studies have identified several different mechanisms for development of cisplatin resistance, including altered DNA repair capacity, increased GSH-based detoxification, and increased metallothionein content. However, none of these mechanisms has been found to be universally associated with the development of cisplatin resistance in tumor cells from different tissue sources. The present study was undertaken to assess whether overexpression of DDH1 or DDH2 (in human ovarian, cervical, lung and germ-cell tumor cell lines) could specifically induce resistance to the platinum drugs in these cell lines. We demonstrated a ubiquitous association of increased expression of DDH1 or DDH2 (as judged by increased enzyme activity in transfected clones) with development of resistance to cisplatin and carboplatin. Moreover, we also found a lack of cross-resistance to anticancer drugs that have a different mode of action including paclitaxel, vincristine, doxorubicin hydrochloride, and melphalan. Although at present it is not clear how DDH is involved in platinum drug resistance, the identification of this gene as a causal factor in a series of cell lines derived from different tumors with different intracellular compositions indicates the importance of deciphering this hitherto undefined pathway which can produce resistance to platinum drugs.
Deng
Hong Bing
HB
Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3400 N. Broad Street, Philadelphia, PA 19140, USA.
Adikari
Mahesha
M
Parekh
Hemant K
HK
Simpkins
Henry
H
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000201:enzymology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism*; D020033:Protein Isoforms; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000201:enzymology; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D000970:Antineoplastic Agents; D016190:Carboplatin; D002945:Cisplatin; D006913:Hydroxysteroid Dehydrogenases; D010088:Oxidoreductases; D020033:Protein Isoforms; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase