title: Ad-p53 enhances the sensitivity of triple-negative breast cancer MDA-MB-468 cells to the EGFR inhibitor gefitinib.
abstract: Triple-negative breast cancer (TNBC) accounts for 20% of all molecular subtypes of breast cancer. Neither endocrine nor anti-HER2 molecular targeting treatment yield promising results. At present, epidermal growth factor receptor (EGFR) inhibitor, as a single agent, is unable to obtain encouraging results in the treatment of TNBC, even though most of these tumors overexpress EGFR. In the present study, we used recombinant human p53 adenovirus (Ad-p53) and EGFR inhibitor gefitinib to treat the TNBC cell line MDA-MB-468. The combined treatment of gefitinib and Ad-p53 synergistically inhibited the proliferation of MDA-MB-468 cells; it restrained colony formation, enhanced cellular apoptosis and arrested the cell cycle in vitro, and decreased tumor burden of xenografts in nude mice. Western blot analysis revealed that Ad-p53 and gefitinib in combination significantly downregulated the phosphorylation of protein kinase B (p-Akt) and upregulated caspase-9 and cleaved caspase-3, while there were minimal effects on the expression of extracellular signal-regulated kinase (ERK) and phosphorylation of ERK (p-ERK). These results suggest that Ad-p53 may block the PI3K/Akt pathway rather than the Raf/MEK/ERK pathway. Importantly, wild-type p53 was able to reverse the drug resistance of MDA-MB-468 cells to gefitinib through inactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. The apoptotic activity induced by this combined treatment may be regulated by caspase cascade-dependent activation.
authors.affiliation: School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong Cancer Hospital, Jinan, Shandong 250117, P.R. China.
authors.forename: Xinzhao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Juxian Hospital of Traditional Chinese Medicine, Rizhao, Shandong 276500, P.R. China.
authors.forename: Hongkuan
authors.initials: H
authors.lastname: Song
authors.affiliation: Department of Biology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yu
authors.affiliation: School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong Cancer Hospital, Jinan, Shandong 250117, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Shandong Cancer Hospital, Jinan, Shandong 250117, P.R. China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Shandong Cancer Hospital, Jinan, Shandong 250117, P.R. China.
authors.forename: Zhaoyun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Shandong Cancer Hospital, Jinan, Shandong 250117, P.R. China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D058539:Phosphatidylinositol 3-Kinase; D000077156:Gefitinib