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Synergistic anti‐tumor effect of paclitaxel with CRM197, an inhibitor of HB‐EGF, in ovarian cancer
Author(s) -
Yagi Hiroshi,
Yotsumoto Fusanori,
Sonoda Kenzo,
Kuroki Masahide,
Mekada Eisuke,
Miyamoto Shingo
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24031
Subject(s) - paclitaxel , mapk/erk pathway , ovarian cancer , cancer research , epidermal growth factor , protein kinase b , p38 mitogen activated protein kinases , heparin binding egf like growth factor , medicine , apoptosis , pharmacology , chemistry , cancer , signal transduction , receptor , biochemistry
Heparin‐binding EGF‐like growth factor (HB‐EGF) plays a pivotal role in tumor growth and clinical outcomes in patients with ovarian cancer, leading to the validation of HB‐EGF as a target for ovarian cancer therapy. In this study, we investigated the anti‐tumor effects of paclitaxel, as an anti‐cancer agent, and CRM197, as a specific inhibitor off HB‐EGF, in ovarian cancer. Paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK through the ectodomain shedding of HB‐EGF in SKOV3 cells. In addition, the overexpression of HB‐EGF in paclitaxel‐treated SKOV3 cells resulted in modulation of paclitaxel‐evoked MAPK signaling, including marked activation of ERK and Akt, and minimized activation of JNK and p38 MAPK, indicating that HB‐EGF is involved in drug sensitivity through the balance of anti‐apoptotic and pro‐apoptotic signals induced by paclitaxel. The combination of paclitaxel with CRM197 had an inhibitory effect on cell proliferation and enhanced apoptosis via the inhibition of ERK and Akt activation and the stimulation of p38 and JNK activation. More prominently, the administration of paclitaxel with CRM197 resulted in synergistic anti‐tumor effects in SKOV3 cells and in SKOV3 cells overexpressing HB‐EGF in xenografted mice. Accordingly, inhibitory agents against HB‐EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer. © 2008 Wiley‐Liss, Inc.