Cisplatin is one of the most effective forms of chemotherapy for advanced stage ovarian cancer although it is generally used as a carboplatin taxol combination. However some patients relapse due to the development of a resistant cell population. In order to identify clinically relevant markers for cisplatin/carboplatin responsiveness, a stable cisplatin-resistant human ovarian carcinoma cell line (2008/C13*) derived from the parental human ovarian carcinoma cell line (2008) was analyzed by microarray analysis followed by semiquantitative RT-PCR. Four genes were found to be upregulated in the cisplatin-resistant ceils: tropomyosin, apolipoprotein J (clusterin), glucose dehydrogenase and dihydro dehydrogenase. All four were upregulated by cisplatin treatment of the 2008 cells. Transfection experiments showed that forced overexpression of only DDH1 induced cisplatin/carboplatin resistance in the parental cell lines. DDH mRNA expression posttransfection was monitored by RT-PCR, and protein expression by enzyme activity assays and immunohistochemistry. Transfection of DDH1 into two other human ovarian carcinoma cell lines, 2780 and SKOV3 resulted in cisplatin carboplatin resistance, but not to other anticancer drugs. Analysis of a human lung squamous cell carcinoma cell line (A549) which has a very high levels of endogenous DDH2 mRNA exhibited a degree of cisplatin resistance greater than that of the 2008/C13* cell line. We propose to continue this work by (a) transfection of non-ovarian cell lines, including Tera-2 (germ cell tumors), A431(cervical carcinoma cells), HTB56 (lung adenocarcinoma ceils) and H69 (small cell lung carcinoma cell), to show that DDH1/2 expression produces cisplatin carboplatin resistance in a variety of cell lines derived from cancers from different organs. (b) We will also attempt to determine the transcriptional control mechanisms responsible for DDH1 upregulation as well as the (c) mechanisms by which DDH1/2 produces resistance to cisplatin (e.g. possible involvement of reactive oxygen species and apoptotic pathways involved). (d) Finally, we will study human ovarian and lung carcinoma tissues prior to and post-chemotherapy (with platinum containing drugs) utilizing monoclonal antibodies to DDH1/2 to determine if DDH expression can be used as a surrogate marker to identify whether, or not a tumor will respond to platinum-based chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA098804-05
Application #
7230959
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wolpert, Mary K
Project Start
2003-07-01
Project End
2010-04-30
Budget Start
2007-07-23
Budget End
2010-04-30
Support Year
5
Fiscal Year
2007
Total Cost
$222,941
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Chen, Jianli; Solomides, Charalambos; Parekh, Hemant et al. (2015) Cisplatin resistance in human cervical, ovarian and lung cancer cells. Cancer Chemother Pharmacol 75:1217-27
Chen, Jianli; Solomides, Charalambos; Simpkins, Henry (2014) Sensitization of mesothelioma cells to platinum-based chemotherapy by GST? knockdown. Biochem Biophys Res Commun 447:77-82
Chen, Jianli; Hurford, Matthew; Mekan, Sabeen et al. (2013) Downregulation of glutathione transferase ? sensitizes lymphoma/leukaemia cells to platinum-based chemotherapy. Br J Haematol 162:135-7
Pallai, Rajash; Simpkins, Henry; Chen, Jianli et al. (2010) The CCAAT box binding transcription factor, nuclear factor-Y (NF-Y) regulates transcription of human aldo-keto reductase 1C1 (AKR1C1) gene. Gene 459:11-23
Chen, Jianli; Emara, Nashwa; Solomides, Charalambos et al. (2010) Resistance to platinum-based chemotherapy in lung cancer cell lines. Cancer Chemother Pharmacol 66:1103-11
Chen, Jianli; Adikari, Mahesha; Pallai, Rajash et al. (2008) Dihydrodiol dehydrogenases regulate the generation of reactive oxygen species and the development of cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 61:979-87
Deng, Hong Bing; Adikari, Mahesha; Parekh, Hemant K et al. (2004) 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. Cancer Chemother Pharmacol 54:301-7