Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation.
New strategies in the therapy for malignant diseases depend on a targeted influence on signal transduction pathways that regulate proliferation, cell growth, differentiation, and apoptosis by the activation of serine/threonine kinases. Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase Cbeta (PKCbeta), is one of these new drugs and causes inhibition of proliferation and induction of apoptosis. Pemetrexed, a multitarget inhibitor of folate pathways, is broadly active in a wide variety of solid tumors. Therefore, the effect of enzastaurin and the combination treatment with pemetrexed was analyzed when applied to the drug-sensitive ovarian cancer cell line HEY and various subclones with drug resistance against cisplatin, etoposide, docetaxel, and paclitaxel, as well as pemetrexed, and gemcitabine. In these novel chemoresistant subclones, the expression of the enzastaurin targets PKCbetaII and glycogen synthase kinase 3beta (GSK3beta) was analyzed. Exposition to enzastaurin showed various inhibitory effects on phosphorylated forms of GSK3beta and the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2. Cell proliferation experiments identified the cell line-specific half-maximal inhibitory concentration values of enzastaurin and a synergistic inhibitory effect by cotreatment with the antifolate pemetrexed. Induction of apoptosis by enzastaurin treatment was investigated by Cell Death Detection ELISA and immunoblot analyses. Simultaneous treatment with pemetrexed resulted in an enhanced inhibition of proliferation and induction of apoptosis even in partial enzastaurin-resistant cells. Therefore, the combinational effect of enzastaurin and pemetrexed can have promise in clinical application to overcome the fast-growing development of resistance to chemotherapy in ovarian cancer.
Bräutigam
Karen
K
Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany.
Bauerschlag
Dirk Olaf
DO
Weigel
Marion Tina
MT
Biernath-Wüpping
Julia
J
Bauknecht
Thomas
T
Arnold
Norbert
N
Maass
Nicolai
N
Meinhold-Heerlein
Ivo
I
Cancer Chemother Pharmacol. 2004 Feb;53(2):133-40
14593497
Invest New Drugs. 2007 Jun;25(3):205-10
17347872
J Biol Chem. 2004 Mar 5;279(10):9233-47
14670956
FEBS Lett. 2001 Nov 9;508(1):126-30
11707282
J Clin Oncol. 2006 Sep 1;24(25):4092-9
16943527
Int Rev Cytol. 2006;251:131-58
16939779
Adv Enzyme Regul. 2005;45:229-55
16143373
Oncogene. 2004 Dec 2;23(56):9062-9
15489897
J Biol Chem. 1992 Aug 25;267(24):16878-82
1324914
Br J Cancer. 2008 Sep 2;99(5):750-9
18728666
J Clin Invest. 2004 Jun;113(11):1615-23
15173888
Cell Signal. 2004 Aug;16(8):951-7
15157674
Pharmacol Res. 2007 Jun;55(6):477-86
17548205
Int J Clin Pharmacol Ther. 2005 Dec;43(12):603-4
16372535
Nature. 1995 Dec 21-28;378(6559):785-9
8524413
Expert Opin Investig Drugs. 2001 Dec;10(12):2117-40
11772309
Nat Rev Cancer. 2007 Apr;7(4):281-94
17384583
Ann Oncol. 2006 May;17 Suppl 5:v29-32
16807459
Cancer Sci. 2008 Mar;99(3):486-96
18167130
Mol Cell Biol. 2002 Apr;22(7):2099-110
11884598
FASEB J. 1995 Apr;9(7):484-96
7737456
J Clin Invest. 1996 Nov 1;98(9):2018-26
8903320
Oncology (Williston Park). 2004 Nov;18(13 Suppl 8):63-5
15655940
Br J Pharmacol. 1999 Mar;126(6):1419-25
10217536
J Clin Oncol. 2000 Sep;18(17):3084-92
10963636
FEBS Lett. 2000 Nov 10;484(3):217-23
11078882
Mol Cancer Ther. 2006 Jul;5(7):1783-9
16891464
Cancer. 2007 Feb 15;109(4):685-91
17219441
Clin Cancer Res. 2004 Jun 15;10(12 Pt 2):4276s-4280s
15217974
Cancer Res. 2005 Aug 15;65(16):7462-9
16103100
Mol Cancer Ther. 2007 Feb;6(2):404-17
17308042
BMC Neurosci. 2005 Feb 02;6:8
15689238
Cancer Res. 2008 Mar 15;68(6):1916-26
18339873
Cancer Lett. 2008 Sep 8;268(1):46-55
18462865
CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96
18287387
J Reprod Med. 2001 Jul;46(7):621-9; discussion 629-30
11499181
Mol Pharmacol. 2005 Jul;68(1):110-8
15795320
J Biol Chem. 2004 Nov 12;279(46):47720-5
15364915
J Endocrinol. 2006 Jan;188(1):79-89
16394177
Mol Cancer Ther. 2008 Jun;7(6):1698-707
18566241
Invest New Drugs. 2008 Jun;26(3):215-22
18000644
J Neurochem. 2008 Sep;106(6):2436-48
18662322
Blood. 2007 Feb 15;109(4):1669-77
17023575
J Invest Dermatol. 2006 Jul;126(7):1641-7
16645590
J Biol Chem. 1995 Jan 20;270(3):987-90
7836418
Biochem J. 1994 Nov 1;303 ( Pt 3):701-4
7980435
J Biol Chem. 2004 May 21;279(21):22118-23
15037605
Bioorg Med Chem Lett. 2003 Jun 2;13(11):1857-9
12749884