Coadministration of the FNIII14 Peptide Synergistically Augments the Anti-Cancer Activity of Chemotherapeutic Drugs by Activating Pro-Apoptotic Bim.
The acquisition of drug resistance mediated by the interaction of tumor cells with the extracellular matrix (ECM), commonly referred to as cell adhesion-mediated drug resistance (CAM-DR), has been observed not only in hematopoietic tumor cells but also in solid tumor cells. We have previously demonstrated that a 22-mer peptide derived from fibronectin, FNIII14, can inhibit cell adhesion through the inactivation of β1 integrin; when coadministered with cytarabine, FNIII14 completely eradicates acute myelogenous leukemia by suppressing CAM-DR. In this study, we show that our FNIII14 peptide also enhances chemotherapy efficacy in solid tumors. Coadministration of FNIII14 synergistically enhances the cytotoxicity of doxorubicin and aclarubicin in mammary tumor and melanoma cells, respectively. The solid tumor cell chemosensitization induced by FNIII14 is dependent upon the upregulation and activation of the pro-apoptotic protein, Bim. Furthermore, the metastasis of tumor cells derived from ventrally transplanted mammary tumor grafts is suppressed by the coadministration of FNIII14 and doxorubicin. These results suggest that the coadministration of our FNIII14 peptide with chemotherapy could achieve efficient solid tumor eradication by increasing chemosensitivity and decreasing metastasis. The major causes of tumor recurrence are the existence of chemotherapy-resistant primary tumor cells and the establishment of secondary metastatic lesions. As such, coadministering FNIII14 with anti-cancer drugs could provide a promising new approach to improve the prognosis of patients with solid tumors.
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.|Translational Research Center, Research Institutes for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
Takuya
http://orcid.org/0000-0001-7420-9534
T
Iyoda
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Yumi
Y
Nagamine
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Yoshitomi
Y
Nakane
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Yuya
Y
Tokita
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Shougo
S
Akari
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Kazuki
K
Otsuka
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Motomichi
M
Fujita
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Keisuke
K
Itagaki
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
You-Ichi
Y
Takizawa
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Hiroaki
H
Orita
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.
Toshiyuki
T
Owaki
Department of Biochemistry, Faculty of Science and Engineering, Saga University, Saga, Saga, Japan.
Jyunichi
J
Taira
Department of Biochemistry, Faculty of Science and Engineering, Saga University, Saga, Saga, Japan.
Ryo
R
Hayashi
Department of Biochemistry, Faculty of Science and Engineering, Saga University, Saga, Saga, Japan.
Hiroaki
H
Kodama
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan.|Translational Research Center, Research Institutes for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
Fumio
F
Fukai
D015250:Aclarubicin / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005353:Fibronectins / Q000008:administration & dosage*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010446:Peptide Fragments / Q000008:administration & dosage
D000970:Antineoplastic Agents; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D005353:Fibronectins; D010446:Peptide Fragments; C501364:fibronectin type III like peptide, human; D015250:Aclarubicin; D004317:Doxorubicin