PMID- 27622612 OWN - NLM STAT- MEDLINE DCOM- 20170808 LR - 20190212 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 9 DP - 2016 TI - Coadministration of the FNIII14 Peptide Synergistically Augments the Anti-Cancer Activity of Chemotherapeutic Drugs by Activating Pro-Apoptotic Bim. PG - e0162525 LID - 10.1371/journal.pone.0162525 [doi] LID - e0162525 AB - 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 beta1 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. FAU - Iyoda, Takuya AU - Iyoda T AUID- ORCID: 0000-0001-7420-9534 AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. AD - Translational Research Center, Research Institutes for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan. FAU - Nagamine, Yumi AU - Nagamine Y AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Nakane, Yoshitomi AU - Nakane Y AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Tokita, Yuya AU - Tokita Y AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Akari, Shougo AU - Akari S AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Otsuka, Kazuki AU - Otsuka K AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Fujita, Motomichi AU - Fujita M AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Itagaki, Keisuke AU - Itagaki K AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Takizawa, You-Ichi AU - Takizawa Y AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Orita, Hiroaki AU - Orita H AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Owaki, Toshiyuki AU - Owaki T AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. FAU - Taira, Jyunichi AU - Taira J AD - Department of Biochemistry, Faculty of Science and Engineering, Saga University, Saga, Saga, Japan. FAU - Hayashi, Ryo AU - Hayashi R AD - Department of Biochemistry, Faculty of Science and Engineering, Saga University, Saga, Saga, Japan. FAU - Kodama, Hiroaki AU - Kodama H AD - Department of Biochemistry, Faculty of Science and Engineering, Saga University, Saga, Saga, Japan. FAU - Fukai, Fumio AU - Fukai F AD - Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan. AD - Translational Research Center, Research Institutes for Science and Technology, Tokyo University of Science, Noda, Chiba, Japan. LA - eng PT - Journal Article DEP - 20160913 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antineoplastic Agents) RN - 0 (Bcl-2-Like Protein 11) RN - 0 (Bcl2l11 protein, mouse) RN - 0 (Fibronectins) RN - 0 (Peptide Fragments) RN - 0 (fibronectin type III like peptide, human) RN - 74KXF8I502 (Aclarubicin) RN - 80168379AG (Doxorubicin) SB - IM MH - Aclarubicin/administration & dosage MH - Animals MH - Antineoplastic Agents/*administration & dosage MH - Apoptosis/drug effects MH - Bcl-2-Like Protein 11/*metabolism MH - Cell Adhesion/drug effects MH - Cell Line, Tumor MH - Doxorubicin/administration & dosage MH - Drug Resistance, Neoplasm MH - Drug Synergism MH - Female MH - Fibronectins/*administration & dosage MH - Humans MH - Mammary Neoplasms, Experimental/drug therapy MH - Melanoma, Experimental/drug therapy MH - Mice MH - Mice, Inbred BALB C MH - Neoplasm Metastasis/prevention & control MH - Peptide Fragments/administration & dosage PMC - PMC5021278 COIS- The authors have declared that no competing interests exist. EDAT- 2016/09/14 06:00 MHDA- 2017/08/09 06:00 PMCR- 2016/09/13 CRDT- 2016/09/14 06:00 PHST- 2016/04/11 00:00 [received] PHST- 2016/08/24 00:00 [accepted] PHST- 2016/09/14 06:00 [entrez] PHST- 2016/09/14 06:00 [pubmed] PHST- 2017/08/09 06:00 [medline] PHST- 2016/09/13 00:00 [pmc-release] AID - PONE-D-16-14530 [pii] AID - 10.1371/journal.pone.0162525 [doi] PST - epublish SO - PLoS One. 2016 Sep 13;11(9):e0162525. doi: 10.1371/journal.pone.0162525. eCollection 2016.