Synergistic anti‐tumor effect of paclitaxel with CRM197, an inhibitor of HB‐EGF, in ovarian cancer

Abstract

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 antitumor 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 paclitaxelevoked 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.

A Novel Anti-Human HB-EGF Monoclonal Antibody with Multiple Antitumor Mechanisms against Ovarian Cancer Cells

“…In addition, Yagi and colleagues recently reported that a chemotherapeutic agent, paclitaxel, induced transient ERK and Akt activation through elevated expression and ectodomain shedding of HB-EGF, resulting in the escape from apoptosis. CRM197, a nontoxic mutant of diphtheria toxin and a specific inhibitor of HB-EGF, showed synergistic antitumor activities with paclitaxel by restoring the sensitivity to paclitaxel in ovarian cancer SKOV-3 cells (13). These studies suggest that an anti-HB-EGF agent is expected to be effective and exert synergistic antitumor activities with chemotherapeutic agents such as paclitaxel against ovarian cancer.…”

“…Ovarian cancer patients with high HB-EGF expression had significantly worse prognosis than those with low HB-EGF expression (7). In addition, HB-EGF is suggested to be involved in tumor resistance against chemotherapeutic agent, paclitaxel (13). These results indicate that inhibition of HB-EGF function is a promising strategy for ovarian cancer therapy.…”

Ovarian Cancer Cell Heparan Sulfate 6-O-Sulfotransferases Regulate an Angiogenic Program Induced by Heparin-binding Epidermal Growth Factor (EGF)-like Growth Factor/EGF Receptor Signaling

“…IL-6 and IL-8 are also important contributors to ovarian cancer angiogenesis, as demonstrated in preclinical models (34 -36). A few preclinical studies demonstrated the efficacy of different HB-EGF inhibitors in the reduction of ovarian tumor growth when administered alone or in combination with paclitaxel (37,38). Thus modulation of expression of multiple angiogenic cytokines through HB-EGF represents an attractive opportunity to target ovarian tumor angiogenesis.…”

Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer

“…Paclitaxel has been reported to activate Akt (Mabuchi et al, 2002;Hokeness et al, 2005) and MAPK pathways (Liu et al, 2001;Kuo et al, 2006;Yagi et al, 2009) and thereby compromises its apoptotic potential, whereas inhibition of these pathways by curcumin increases susceptibility of cancer cells to chemotherapeutic agents (Bava et al, 2005;Aggarwal et al, 2006;Gagnon et al, 2008). Although activated JNK contributes to some apoptotic responses, the JNK-dependent apoptotic signaling pathways can be blocked by activation of NF-kB and Akt pathways (Xia et al, 1995).…”