TY - JOUR
T1 - Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation
AU - Bräutigam, Karen
AU - Bauerschlag, Dirk
AU - Weigel, Marion Tina
AU - Biernath-Wüpping, Julia
AU - Bauknecht, Thomas
AU - Arnold, Norbert
AU - Maass, Nicolai
AU - Meinhold-Heerlein, Ivo
N1 - Funding Information:
Address all correspondence to: Karen Braeutigam, Burnham Institute for Medical Research, 10901 N Torrey Pines Rd, La Jolla, CA 92037. E-mail: [email protected] 1The authors thank the unrestricted research grant from Lilly GmbH Deutschland that supported this study. 2This article refers to supplementary materials, which are designated by Table W1 and Figures W1 and W2 and are available online at www.transonc.com. Received 17 February 2009; Revised 1 April 2009; Accepted 7 April 2009 Copyright © 2009 Neoplasia Press, Inc. Open access under CC BY-NC-ND license. 1944-7124 DOI 10.1593/tlo.09121
PY - 2009/9
Y1 - 2009/9
N2 - 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 Cβ (PKCβ), 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 PKCβII and glycogen synthase kinase 3β (GSK3β) was analyzed. Exposition to enzastaurin showed various inhibitory effects on phosphorylated forms of GSK3β 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.
AB - 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 Cβ (PKCβ), 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 PKCβII and glycogen synthase kinase 3β (GSK3β) was analyzed. Exposition to enzastaurin showed various inhibitory effects on phosphorylated forms of GSK3β 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.
UR - http://www.scopus.com/inward/record.url?scp=77953398189&partnerID=8YFLogxK
U2 - 10.1593/tlo.09121
DO - 10.1593/tlo.09121
M3 - Journal articles
AN - SCOPUS:77953398189
SN - 1936-5233
VL - 2
SP - 164
EP - 173
JO - Translational Oncology
JF - Translational Oncology
IS - 3
ER -