Identification of genes associated with platinum drug sensitivity and resistance in human ovarian cancer cells.
Platinum-based chemotherapeutic regimens are ultimately unsuccessful due to intrinsic or acquired drug resistance. Understanding the molecular basis for platinum drug sensitivity/resistance is necessary for the development of new drugs and therapeutic regimens. In an effort to identify such determinants, we evaluated the expression of approximately 4000 genes using cDNA microarray screening in a panel of 14 unrelated human ovarian cancer cell lines derived from patients who were either untreated or treated with platinum-based chemotherapy. These data were analysed relative to the sensitivities of the cells to four platinum drugs (cis-diamminedichloroplatinum (cisplatin), carboplatin, DACH-(oxalato)platinum (II) (oxaliplatin) and cis-diamminedichloro (2-methylpyridine) platinum (II) (AMD473)) as well as the proliferation rate of the cells. Correlation analysis of the microarray data with respect to drug sensitivity and resistance revealed a significant association of Stat1 expression with decreased sensitivity to cisplatin (r=0.65) and AMD473 (r=0.76). These results were confirmed by quantitative RT-PCR and Western blot analyses. To study the functional significance of these findings, the full-length Stat1 cDNA was transfected into drug-sensitive A2780 human ovarian cancer cells. The resulting clones that exhibited increased Stat1 expression were three- to five-fold resistant to cisplatin and AMD473 as compared to the parental cells. The effect of inhibiting Jak/Stat signalling on platinum drug sensitivity was investigated using the Janus kinase inhibitor, AG490. Pretreatment of platinum-resistant cells with AG490 resulted in significant increased sensitivity to AMD473, but not to cisplatin or oxaliplatin. Overall, the results indicate that cDNA microarray analysis may be used successfully to identify determinants of drug sensitivity/resistance and future functional studies of other candidate genes from this database may lead to an increased understanding of the drug resistance phenotype.
Roberts
D
D
University of Pennsylvania Cancer Center, Philadelphia, PA 19104, USA.
Schick
J
J
Conway
S
S
Biade
S
S
Laub
P B
PB
Stevenson
J P
JP
Hamilton
T C
TC
O'Dwyer
P J
PJ
Johnson
S W
SW
D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009944:Organoplatinum Compounds
Biochem Pharmacol. 1996 Dec 24;52(12):1855-65
8951344
Gan. 1976 Dec;67(6):921-2
1021513
Nat Genet. 2000 Mar;24(3):236-44
10700175
Semin Oncol. 1999 Dec;26(6):647-62
10606258
J Immunol Methods. 1989 May 12;119(2):203-10
2470825
Anal Biochem. 1995 Feb 10;225(1):163-4
7539982
Recent Results Cancer Res. 1980;74:146-55
7444136
Drug Resist Updat. 1998;1(4):243-54
16904407
Cancer Genet Cytogenet. 1984 Aug;12(4):321-7
6744227
Annu Rev Immunol. 1998;16:293-322
9597132
Br J Haematol. 2000 Jun;109(4):823-8
10929036
Eur J Haematol. 2001 Aug;67(2):63-71
11722592
Cancer Lett. 2003 Nov 10;201(1):107-16
14580692
Chem Biol Interact. 1972 Nov;5(6):415-24
4652593
Nat Genet. 2000 Mar;24(3):227-35
10700174
Mol Cell Biol. 2000 Jan;20(2):583-93
10611237
Head Neck. 2003 Mar;25(3):187-93
12599285
Cancer Res. 2001 Sep 1;61(17):6540-7
11522652
Am J Obstet Gynecol. 2003 May;188(5):1283-90
12748499
Eur J Cancer. 1993;29A(3):395-9
8398340
Blood. 2000 Feb 15;95(4):1435-42
10666222
Br J Cancer. 1998;77(3):366-73
9472630
J Biol Chem. 2000 Mar 17;275(11):7988-93
10713117
Cancer Res. 1997 Mar 1;57(5):850-6
9041185
Cancer Res. 2002 Feb 15;62(4):1139-47
11861395
FEBS Lett. 2000 Jun 23;475(3):209-12
10869558
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
9843981
Clin Cancer Res. 1997 Nov;3(11):2063-74
9815598
Cancer Res. 2000 Mar 1;60(5):1225-8
10728680
In Vivo. 1997 Nov-Dec;11(6):463-72
9509296
Oncogene. 2001 Nov 29;20(55):7925-34
11753675
Oncogene. 2001 May 3;20(20):2499-513
11420660
Anal Biochem. 1987 Apr;162(1):156-9
2440339