title: Cross-reacting material 197 reverses the resistance to paclitaxel in paclitaxel-resistant human ovarian cancer.
abstract: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has been proven to be a promising chemotherapeutic target for ovarian cancer. Our previous studies have demonstrated that inhibition of HB-EGF by the special inhibitor, cross-reacting material 197 (CRM197), potently inhibits the anti-tumor activity in paclitaxel-resistant ovarian cancer. Here, we found that inhibition of HB-EGF by CRM197 significantly reverses the resistance to paclitaxel in paclitaxel-resistant ovarian carcinoma cell line (A2780/Taxol). A2780/Taxol cells over-expressed HB-EGF and epidermal growth factor receptor (EGFR) and CRM197 notably suppressed the expression of HB-EGF and EGFR. Experiments performed in vitro and in vivo further suggested that CRM197 markedly down-regulated the ATP-binding cassette sub-family B member 1 (ABCB1/MDR1) messenger RNA (mRNA) expression (P = 0.01), plasma membrane glycoprotein (P-gp) protein (P = 0.009), and P-gp-mediated efflux (P = 0.007) through inhibition of nuclear factor-κB (NF-κB) expression, which were classical chemoresistance-related targets with respect to paclitaxel therapy. Meanwhile, inhibition of HB-EGF enhanced caspase-3 activity to induce apoptosis via MDR1 inhibition in A2780/Taxol cells (P = 0.038). Collectively, HB-EGF is a molecular target for the resistance of ovarian cancer to paclitaxel and CRM197 as a HB-EGF-targeted agent might be a chemosensitizing agent for paclitaxel-resistant ovarian carcinoma. Our findings provide novel possible mechanisms for HB-EGF to be a target to restore the chemosensitivity to paclitaxel.
authors.affiliation: Department of Gynecology and Obstetrics, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China.
authors.forename: Xiao-Han
authors.initials: XH
authors.lastname: Tang
authors.affiliation: Department of Gynecology and Obstetrics, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China.
authors.forename: Suo
authors.initials: S
authors.lastname: Deng
authors.affiliation: Department of Gynecology and Obstetrics, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Gynecology and Obstetrics, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, 150001, China. lumeisong0417@163.com.
authors.forename: Mei-Song
authors.initials: MS
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001426:Bacterial Proteins / Q000008:administration & dosage*; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics*; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D001426:Bacterial Proteins; D066257:Heparin-binding EGF-like Growth Factor; C028581:CRM197 (non-toxic variant of diphtheria toxin); C512478:EGFR protein, human; D066246:ErbB Receptors; D053148:Caspase 3; D017239:Paclitaxel
keywords: ATP-binding cassette sub-family B member 1; Chemotherapy resistance; Cross-reacting material 197; Heparin-binding epidermal growth factor-like growth factor; Nuclear factor-κB; Ovarian cancer