Novartis, Basel, Switzerland) is a small-molecule tyrosine
kinase inhibitor with activity against ABL, BCR-ABL, c-KIT,
and PDGFRα. Several clinical trials have evaluated the
efficacy and safety of imatinib in patients with ovarian
carcinoma who have persistent or recurrent disease following
front-line platinum/taxane based chemotherapy. However, there
is limited pre-clinical and clinical data on the molecular
targets and action of imatinib in ovarian cancer. Materials and
Methods: Human ovarian cancer cells (A2780) were treated
with imatinib mesylate for either 6 or 24 h. We employed a 2D
(two-dimensional) gel electrophoresis and mass spectrometry-
based proteomics approach to identify protein expression
patterns and signaling pathways that were altered in response
to imatinib. Cells were analyzed for PDGFRα and AKT
expression, which were then correlated with imatinib sensitivity.
Results: Using 2D gel electrophoresis of overlapping pH
ranges from pH 4 to 11, about 4,000 protein spots could be
analyzed reproducibly. Proteins whose levels changed between
two fold to 30 fold were grouped according to whether changes
were in the same direction at both time points of treatment with
respect to the control, or changed their levels only at one of the
time points. Conclusion: Differentially regulated proteins
following imatinib treatment of A2780 cells involved the
regulation of actin cytoskeleton, metabolic pathways, cell cycle,
cell proliferation, apoptosis, cell junctions, and signal
transduction. Thus, exposure of cells to imatinib produces
complex changes in the cell that require further investigation.
Ovarian carcinoma is the fifth leading cause of cancer death
among women in the United States and the most common
cause of death among gynecologic malignancies (1).
Ovarian cancer affects about 15 women for every 100,000
women under the age of 40 and over 50 women for every
100,000 women above the age of 70 (1). The five-year
survival rate for patients with advanced stage ovarian cancer
is only 29% which is in contrast to the women with tumors
confined to the ovaries exceeding 90% (1). The cornerstone
of management for advanced ovarian cancer involves
cytoreductive surgery followed by standard adjuvant
chemotherapy that consists of the combination of a taxane
with a platinum-based drug (2). Despite this initially
effective combination therapy, a majority of the advanced
ovarian cancer patients will relapse (3). Therapeutic options
for relapsed ovarian cancer patients are limited. While a
number of agents have demonstrated activity in second-line
treatment of recurrent ovarian carcinoma, response rates are
low and usually of short duration (3). Molecular targeting
approaches manipulating the biology of the disease may
hold promise for the future. Therefore, the development of
novel treatment strategies in advanced disease is critical to
improve patient survival.
Platelet-derived growth factor (PDGF) is a potent mitogen
with two isoforms PDGF-A and PDGF-B, and differentially
binds to two structurally related receptor tyrosine kinases
(RTKs), PDGFRα and PDGFRβ. Ligand-activated receptors
trigger downstream signal transduction pathways, including
phosphatidylinositol 3-kinase (PI3K)/ AKT and, extracellular
signal-regulated kinase 1/2 (ERK1/2) which promote cell
proliferation and survival. Several groups reported the
differential expression of PDGF, PDGFRα, and PDGFRβ in
ovarian cancer compared to normal ovarian epithelium (4-7).
Matei et al. found that about 39% of ovarian tumors express
PDGFRα by immunohistochemistry (8). Another study
showed that approximately 58% of epithelial ovarian cancers
Correspondence to: Anthony T. Yeung, Ph.D., Fox Chase Cancer
Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, U.S.A.
Tel: +215 728 2488, Fax: +215 728 3647, e-mail: AT_Yeung@
Key Words:Imatinib mesylate, ovarian cancer, PDGFR, proteomics.
CANCER GENOMICS & PROTEOMICS 5: 137-150 (2008)
Molecular Mechanisms of Action of Imatinib Mesylate
in Human Ovarian Cancer:A Proteomic Analysis
BHAVINKUMAR B. PATEL1, ΥΙΝ Α. HE1, XIN-MING LI1, ANDREY FROLOV3,
LISA VANDERVEER2, CAROLYN SLATER2, RUSSELL J. SCHILDER2,
MARGARET VON MEHREN2, ANDREW K. GODWIN2and ANTHONY T. YEUNG1
Division of1Basic Science, and2Medical Science, Fox Chase Cancer Center,
333 Cottman Avenue, Philadelphia, Pennsylvania;
3Department of Surgery, University of Alabama at Birmingham,
1824 6th Ave South, Birmingham, Alabama, U.S.A.
(EOC) express PDGFRα and 28% of those express PDGFRβ
as determined by immunohistochemistry (7). Patients with
PDGFRα positive ovarian cancers have demonstrated an
overall shorter survival compared to those whose tumors were
PDGFRα negative (5).
Imatinib (Gleevec, Novartis, Basel, Switzerland), is a 2-
phenylaminopyrimidine derivative that is a RTK inhibitor
with potent activity against ABL (including the BCR-ABL
fusion protein found in chronic myelogenous leukemia
(CML)), PDGFRα, PDGFRβ, and c-KIT (9, 10). It is
approved for the treatment of CML and gastrointestinal
stromal tumor (GIST) (11), and is under evaluation in
clinical trials for ovarian cancer (http://clinicaltrials.gov/
ct2/home, NCT00510653, NCT00041041, NCT00036751),
malignant gliomas, prostate cancer, and carcinoid tumor (12-
17). About 80-90% patients with metastatic gastrointestinal
stromal tumor respond, or achieve stabilization of tumor
growth, to continuous imatinib therapy with daily dose of
400 mg to 600 mg (18-20). Matei et al. showed that imatinib
inhibits the growth of ovarian cancer cells in a PDGFRα
positive cell culture but has no effect on PDGFR negative
cell culture, at clinically relevant concentrations (8).
In this study, we utilized a proteomic approach to test the
cellular response of imatinib to obtain some insights into how
this drug might influence the proteome of ovarian cancer cells.
Two-dimensional (2D) gel electrophoresis-based approach is
a powerful and practical proteomics tool for qualitative and
quantitative comparisons of proteomes under different
conditions to unravel dynamic biological processes (21). By
comparing spot intensities from different samples, changes in
the level of individual proteins expression can be quantified
enabling the visualization and identification of several
thousand proteins on a single gel (22). We thus employed a
2D gel electrophoresis and MALDI-TOF peptide mass
fingerprinting proteomic approach to identify the protein
expression profile in the A2780 human ovarian cancer cell line
treated and untreated with imatinib. The combination of 2D
gel proteomics and mass spectrometry resulted in the
identification of 1010 proteins, with 501 non-redundant
entities and about 509 isoforms. All data are provided at our
web site (http://yeung.fccc.edu).
Materials and Methods
Cell lines and response to imatinib treatment. The ovarian cancer cell
lines, A2780, OVCAR3, and OVCAR10, were cultured as previously
described (23). For growth analysis, cells were seeded at 6.5x105
cells per 60 mm dish. Imatinib (dissolved in water to a stock
concentration of 10 mM) was added directly to the media to achieve
the final concentration of 1 or 10 μM. Cells were refed with
conditioned media with or without drug every 12 hours. Cells were
then harvested and stained for the cell number and cell viability
Burlingame, CA, USA). The cells were counted using a Guava
Personal Cytometer and the data analyzed using the Guava CytoSoft
software package (Guava Technology Inc., Burlingame, CA, USA).
For cell cycle analysis, cells were trypsinized, centrifuged, and fixed
in 70% ethanol at 4˚C. Cell pellets were re-suspended in 50 μg/ml
propidium iodide in PBS for 30 min at 4˚C. The stained cells were
analyzed by flow cytometry performed on a FACScan and the data
analyzed with Cell Quest software (Becton Dickinson). Each
experiment was performed in triplicates and repeated at least 2 times.
Western blot analysis. Cell lysate preparation and western blot
analysis was performed as previously described (24). Anti-β-actin
monoclonal antibodies (Sigma, St. Louis, MO, USA) were used at
a dilution of 1:5,000 in 5% dried milk. Anti Phospho-PDGFRα (Tyr
754) rabbit polyclonal antibody (Santa Cruz Biotechnology) was
antibodies (Cell Signaling) were each used at a dilution of 1:1000 in
5% BSA. Quantification of Western blots were performed using the
“NIH image” software as described by the manufacturer.
at 1:500dilution in5% BSA. Anti-AKT,anti-
Preparation of protein sample for 2-DE electrophoresis. A2780 cell
cultures were divided into: a) control untreated for 24 hours; b)
cultured without imatinib for 12 hours then with 10 μM imatinib for
6 hours; c) imatinib (10 μM) treated for 24 hours. All cell pellets
were washed 3 times with cold 1x PBS before storage in –80˚C.
Protein extracts from these stored cell pellets were obtained by
using 2D-protein extraction buffer (7 M urea, 2 M thiourea, 65 mM
CHAPS, 8 mM PMSF, 97.4 mM hydroxyethyldisulfide). For 200
mg wet weight cell pellet, 2x500 μl extraction buffer was used. The
detailed protocol for protein extraction with acetone precipitation
was described previously (25). Protein concentration was
determined by a modified Bradford assay, using a standard curve
based on BSA dissolved in the same 2D sample buffer.
Two-dimensional gel electrophoresis. We used established standard
operating procedures (SOP) for 2D gel electrophoresis and their
analyses (25, 26). All imatinib treated and untreated protein samples
were resolved on 2D gels with 3 overlapped pH gradients in the first
dimension: pH 4-7, pH 5-8 and pH 6-11. The first dimension was
carried out with analytical loading of 100 μg protein using in-sample
rehydration method for pH 4-7 (17 cm IPGs) and pH 5-8 strips (17
cm IPGs), and Cup-loading method for pH 6-11 strips (18 cm IPGs).
The second dimension was performed using 12% polyacrylamide SDS
gel (20 cm x 20 cm x 1 mm). Proteins in the gels were visualized with
Sypro Ruby fluorescence stain (Bio-Rad) and scanned with a Perkin
Elmer ProXPRESS (Perkin Elmer) scanner.All gels in this study were
run in triplicates per pH range, and the two best gels of each sample
were used for further image analysis.
Image analyses and protein spot identification. The detail methods
for image analysis and protein identification by mass spectrometry
were described previously (25, 26). Briefly, 2D gel image analysis
was done by Progenesis Discovery workstation software (v2003.02,
Nonlinear Dynamics Ltd., Newcastle, UK) assisted by manual
editing. The protein spot picking list was generated through image
analysis and spot cutting for multiples of 96 spots performed by
ProPic Robot (Genomic Solutions, MI, USA). The automated in-
gel trypsin digestion of protein spots was facilitated by the robot
Tecan Genesis (Tecan US, Durham, NC). Proteins were identified
using MALDI-TOF mass spectrometry peptide mass fingerprinting
CANCERGENOMICS &PROTEOMICS 5: 137-150 (2008)
induce the expression of cell cycle-regulating genes, such as
cyclin-dependent kinases and cyclin D1 and others that may
promote cell cycle progression (44).
In summary, the cellular response to imatinib treatment
leading to growth arrest of A2780 ovarian cancer cell line is
complex, many of the changes in the proteome occur at the
level of individual isoforms of each protein. Thus a focus on
post-translational modifications will be important to future
Furthermore, these studies emphasize that despite expression
of the receptors targeted by imatinib other downstream
pathways are likely to be co-activated in these tumors and that
redundant inputs drive and maintain downstream signaling,
thereby limiting the efficacy of therapies targeting a single or a
few RTKs (45). This does not mean that agents with minimal
single activity may not be useful, but that they will need to be
combined in rationale approaches with other drugs. Thus,
effective therapy of ovarian cancer will undoubtedly require
combined regimens targeting multiple RTKs. Our proteomic
studies begin to provide such insights in pathways that could
be targeted in combination with imatinib to ultimately improve
the treatment of patients with ovarian cancer.
ofthe anti-cancer mechanismsof imatinib.
This work was supported in part by the Ovarian Cancer SPORE at
FCCC (P50 CA083638), Institutional Core Grant P30CA06927, the
Fannie E. Rippel Foundation, the Shöller Foundation, Ovarian Cancer
Research Fund, Tobacco Settlement Funds from the Commonwealth
of Pennsylvania, the Pew Charitable Trust, and the Kresge Foundation.
The authors acknowledge the use of the proteomics equipment in
the Biochemistry and Biotechnology Facility of the Fox Chase
1 Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ:
Cancer statistics, 2007. CA Cancer J Clin 57: 43-66, 2007.
McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE,
Look KY, Clarke-Pearson DL and Davidson M: Cyclo-
phosphamide and cisplatin compared with paclitaxel and
cisplatin in patients with stage III and stage IV ovarian cancer. N
Engl J Med 334: 1-6, 1996.
Bookman MA: Developmental chemotherapy and management
of recurrent ovarian cancer. J Clin Oncol 21: 149s-167s, 2003.
Apte SM, Bucana CD, Killion JJ, Gershenson DM and Fidler I:
J. Expression of platelet-derived growth factor and activated
receptor in clinical specimens of epithelial ovarian cancer and
ovarian carcinoma cell lines. Gynecol Oncol 93: 78-86, 2004.
Henriksen R, Funa K, Wilander E, Backstrom T, Ridderheim M
and Oberg K: Expression and prognostic significance of platelet-
derived growth factor and its receptors in epithelial ovarian
neoplasms. Cancer Res 53: 4550-4554, 1993.
Matei D, Emerson RE, Lai YC, Baldridge LA, Rao J,
Yiannoutsos C and Donner DD: Autocrine activation of
PDGFRalpha promotes the progression of ovarian cancer.
Oncogene 25: 2060-2069, 2006.
7 Wilczynski SP, Chen YY, Chen W, Howell SB, Shively JE and
Alberts DS: Expression and mutational analysis of tyrosine
kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian
cancers. Hum Pathol 36: 242-249, 2005.
Matei D, Chang DD and Jeng MH: Imatinib mesylate (Gleevec)
inhibits ovarian cancer cell growth through a mechanism
dependent on platelet-derived growth factor receptor alpha and
Akt inactivation. Clin Cancer Res 10: 681-690, 2004.
Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S,
Druker BJ and Lydon NB: Abl protein-tyrosine kinase inhibitor
STI571 inhibits in vitro signal transduction mediated by c-kit
and platelet-derived growth factor receptors. J Pharmacol Exp
Ther 295: 139-145, 2000.
10 Buchdunger E, O’Reilly T and Wood J: Pharmacology of
imatinib (STI571). Eur J Cancer 38: S28-36, 2002.
11 Dushkin H and Schilder RJ: Imatinib mesylate and its potential
implications for gynecologic cancers. Curr Treat Options Oncol
6: 115-120, 2005.
12 Bajaj GK, Zhang Z, Garrett-Mayer E, Drew R, Sinibaldi V, Pili R,
Denmeade SR, Carducci MA, Eisenberger MA and DeWeese TL:
Phase II study of imatinib mesylate in patients with prostate cancer
with evidence of biochemical relapse after definitive radical
retropubic prostatectomy or radiotherapy. Urology 69: 526-31, 2007.
13 Coleman RL, Broaddus RR, Bodurka DC, Wolf JK, Burke TW,
Kavanagh JJ, Levenback CF and Gershenson DM: Phase II trial
of imatinib mesylate in patients with recurrent platinum- and
taxane-resistant epithelial ovarian and primary peritoneal
cancers. Gynecol Oncol 101: 126-31. Epub 2005 Nov 3, 2006.
14 Pollack IF, Jakacki RI, Blaney SM, Hancock ML, Kieran MW,
Phillips P, Kun LE, Friedman H, Packer R, Banerjee A, Geyer
JR, Goldman S, Poussaint TY, Krasin MJ, Wang Y, Hayes M,
Murgo A, Weiner S and Boyett JM: Phase I trial of imatinib in
children with newly diagnosed brainstem and recurrent
malignant gliomas: a Pediatric Brain Tumor Consortium report.
Neuro Oncol 9: 145-160. Epub 2007 Feb 9, 2007.
15 Posadas EM, Kwitkowski V, Kotz HL, Espina V, Minasian L,
Tchabo N, Premkumar A, Hussain MM, Chang R, Steinberg SM
and Kohn EC:A prospective analysis of imatinib-induced c-KIT
modulation in ovarian cancer: a phase II clinical study with
proteomic profiling. Cancer 110: 309-317, 2007.
16 Yao JC, Zhang JX, Rashid A,Yeung SC, Szklaruk J, Hess K, Xie
K, Ellis L, Abbruzzese JL and Ajani JA: Clinical and in vitro
studies of imatinib in advanced carcinoid tumors. Clin Cancer
Res 13: 234-240, 2007.
17 Alberts DS, Liu PY, Wilczynski SP, Jang A, Moon J, Ward JH,
Beck JT, Clouser M and Markman M: Phase II trial of imatinib
mesylate in recurrent, biomarker positive, ovarian cancer
(Southwest Oncology Group Protocol S0211). Int J Gynecol
Cancer, 17: 784-788, 2007.
18 Joensuu H: Gastrointestinal stromal tumor (GIST). Ann Oncol,
17: x280-286, 2006.
19 Tarn C and Godwin AK: Molecular research directions in the
management of gastrointestinal stromal tumors. Curr Treat
Options Oncol 6: 473-486, 2005.
20 Tarn C and Godwin AK: The molecular pathogenesis of
gastrointestinal stromal tumors. Clin Colorectal Cancer 6: S7-
21 Carrette O, Burkhard PR, Sanchez JC and Hochstrasser DF:
State-of-the-art two-dimensional gel electrophoresis: a key tool
of proteomics research. Nat Protoc 1: 812-823, 2006.
CANCERGENOMICS &PROTEOMICS 5: 137-150 (2008)
22 Gorg A, Obermaier C, Boguth G, Harder A, Scheibe B,
Wildgruber R and Weiss W: The current state of two-
dimensional electrophoresis with immobilized pH gradients.
Electrophoresis 21: 1037-1053, 2000.
23 Godwin AK, Testa JR, Handel LM, Liu Z, Vanderveer LA,
Tracey PA and Hamilton TC: High resistance to cisplatin in
human ovarian cancer cell lines is associated with marked
increase of glutathione synthesis. Proc Natl Acad Sci USA 89:
24 Frolov A, Chahwan S, Ochs M, Arnoletti JP, Pan ZZ, Favorova
O, Fletcher J, von Mehren M, Eisenberg B and Godwin AK:
Response markers and the molecular mechanisms of action of
Gleevec in gastrointestinal stromal tumors. Mol Cancer Ther 2:
25 Li XM, Patel BB, Blagoi EL, Patterson MD, Seehozer SH,
Zhang T, Damle S, Gao Z, Boman B and Yeung AT: Analyzing
alkaline proteins in human colon crypt proteome. J Proteome
Res 3: 821-833, 2004.
26 Patel BB, Li XM, Dixon MP, Blagoi EL, Seeholzer SH, Chen,Y,
Miller CG, He YA, Tetruashvily M, Chaudhry AH, Ke E, Xie J,
Cooper H, Bellacosa A, Clapper ML, Boman BM, Zhang T,
Litwin S, Ross EA, Conrad P, Crowell JA, Kopelovich L,
Knudson A and Yeung AT: Searchable High-Resolution 2D Gel
Proteome of the Human Colon Crypt. J Proteome Res 6: 2232-
27 Al-Shahrour F, Diaz-Uriarte R and Dopazo J: FatiGO: a web
tool for finding significant associations of Gene Ontology terms
with groups of genes. Bioinformatics 20: 578-580, 2004.
28 Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry
JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA,
Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC,
Richardson JE, Ringwald M, Rubin GM and Sherlock G: Gene
ontology: tool for the unification of biology. The Gene Ontology
Consortium. Nat Genet 25: 25-29, 2000.
29 Kanehisa M, Goto S, Kawashima S, Okuno Y and Hattori M:
The KEGG resource for deciphering the genome. Nucleic Acids
Res 32: D277-280, 2004.
30 Peri S, Navarro JD, Kristiansen TZ, Amanchy R, Surendranath
V, Muthusamy B, Gandhi TK, Chandrika KN, Deshpande N,
Suresh S, Rashmi BP, Shanker K, Padma N, Niranjan V, Harsha
HC, Talreja N, Vrushabendra BM, Ramya MA, Yatish AJ, Joy
M, Shivashankar HN, Kavitha MP, Menezes M, Choudhury DR,
Ghosh N, Saravana R, Chandran S, Mohan S, Jonnalagadda CK,
Prasad CK, Kumar-Sinha C, Deshpande KS and Pandey A:
Human protein reference database as a discovery resource for
proteomics. Nucleic Acids Res 32: D497-501, 2004.
31 Janssens V and Goris J: Protein phosphatase 2A: a highly
regulated family of serine/threonine phosphatases implicated in
cell growth and signalling. Biochem J 353: 417-439, 2001.
32 Millward TA, Zolnierowicz S and Hemmings BA: Regulation of
protein kinase cascades by protein phosphatase 2A. Trends
Biochem Sci 24: 186-191, 1999.
33 Van Hoof C and Goris J: Phosphatases in apoptosis: to be or not
to be, PP2A is in the heart of the question. Biochim Biophys
Acta 1640: 97-104, 2003.
34 Cohen PT: Protein phosphatase 1–targeted in many directions. J
Cell Sci 115: 241-256, 2002.
35 Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B,
Wright A, Vanderbilt C and Cobb MH: MAP kinases. Chem Rev
101: 2449-2476, 2001.
36 Robinson-White A, Hundley TR, Shiferaw M, Bertherat J,
Sandrini F and Stratakis CA: Protein kinase-A activity in
PRKAR1A-mutant cells, and regulation of mitogen-activated
protein kinases ERK1/2. Hum Mol Genet 12: 1475-1484, 2003.
37 Robinson-White AJ, Leitner WW, Aleem E, Kaldis P, Bossis I
and Stratakis CA: PRKAR1A inactivation leads to increased
proliferation and decreased apoptosis in human B lymphocytes.
Cancer Res 66: 10603-10612, 2006.
38 Jiang PS andYung BY: Down-regulation of nucleophosmin/B23
mRNA delays the entry of cells into mitosis. Biochem Biophys
Res Commun 257: 865-870, 1999.
39 You BJ, Huang IJ, Liu WH, Hung YB, Chang JH and Yung BY:
Decrease in nucleophosmin/B23 mRNA and telomerase activity
during indomethacin-induced apoptosis of gastric KATO-III
cancer cells. Naunyn Schmiedebergs Arch Pharmacol 360: 683-
40 Paunesku T, Mittal S, Protic M, Oryhon J, Korolev SV,
Joachimiak A and Woloschak GE: Proliferating cell nuclear
antigen (PCNA): ringmaster of the genome. Int J Radiat Biol,
77: 1007-1021, 2001.
41 Steensgaard P, Garre M, Muradore I, Transidico P, Nigg EA,
Kitagawa K, Earnshaw WC, Faretta M and Musacchio A: Sgt1 is
required for human kinetochore assembly. EMBO Rep 5: 626-
631, 2004. Epub 2004 May 7, 2004.
42 Young TW, Mei FC, Rosen DG, Yang G, Li N, Liu J and Cheng
X: Up-regulation of tumor susceptibility gene 101 protein in
ovarian carcinomas revealed by proteomics analyses. Mol Cell
Proteomics 6: 294-304, 2007. Epub 2006 Nov 16, 2007.
43 Schilder RJ, Sill MW, Lee RB, Shaw TJ, Senterman MK, Klein-
Szanto AJ, Miner Z and Vanderhyden BC: A phase II evaluation
of imatinib mesylate (IND #61135, NSC #716051) in the
treatment of recurrent or persistent epithelial ovarian or primary
peritoneal carcinoma: a gynecologic oncology group study. J
Clin Oncol, in press, 2008.
44 Roberts PJ and Der CJ: Targeting the Raf-MEK-ERK mitogen-
activated protein kinase cascade for the treatment of cancer.
Oncogene 26: 3291-310, 2007.
45 Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti
AH, Wiedemeyer R, Stegh AH, Bradner JE, Ligon KL, Brennan
C, Chin L and DePinho RA: Coactivation of receptor tyrosine
kinases affects the response of tumor cells to targeted therapies.
Science 318: 287-290, 2007. Epub 2007 Sep 13, 2007.
Received February 29, 2008
Accepted March 7, 2008
Patel et al: Proteomics of Imatinib Treatment in Human Ovarian Cancer