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Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3.
Cancers (Basel). 2020 Feb 24; 12(2)C

Abstract

Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

Authors+Show Affiliations

Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan. Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.On-Chip Biotechnologies, Co., Ltd. Tokyo 184-0012, Japan.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan. ODAPUS (Okayama University Dental School Short-Term-Study-Abroad Program for Undergraduate Students) from Medical School, University of Western Brittany, 29238 Brest, France.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan. Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan. Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.Department of Dental Pharmacology, Matsumoto Dental University, Shiojiri 399-0704, Japan.Advanced Research Center for Oral and Craniofacial Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.Department of Dental Pharmacology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8525, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32102440

Citation

Sogawa, Chiharu, et al. "Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis By Acting On SLC6A3/DAT and Reducing STAT3." Cancers, vol. 12, no. 2, 2020.
Sogawa C, Eguchi T, Tran MT, et al. Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3. Cancers (Basel). 2020;12(2).
Sogawa, C., Eguchi, T., Tran, M. T., Ishige, M., Trin, K., Okusha, Y., Taha, E. A., Lu, Y., Kawai, H., Sogawa, N., Takigawa, M., Calderwood, S. K., Okamoto, K., & Kozaki, K. I. (2020). Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3. Cancers, 12(2). https://doi.org/10.3390/cancers12020523
Sogawa C, et al. Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis By Acting On SLC6A3/DAT and Reducing STAT3. Cancers (Basel). 2020 Feb 24;12(2) PubMed PMID: 32102440.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3. AU - Sogawa,Chiharu, AU - Eguchi,Takanori, AU - Tran,Manh Tien, AU - Ishige,Masayuki, AU - Trin,Kilian, AU - Okusha,Yuka, AU - Taha,Eman Ahmed, AU - Lu,Yanyin, AU - Kawai,Hotaka, AU - Sogawa,Norio, AU - Takigawa,Masaharu, AU - Calderwood,Stuart K, AU - Okamoto,Kuniaki, AU - Kozaki,Ken-Ichi, Y1 - 2020/02/24/ PY - 2020/02/03/received PY - 2020/02/18/revised PY - 2020/02/20/accepted PY - 2020/2/28/entrez PY - 2020/2/28/pubmed PY - 2020/2/28/medline KW - benztropine KW - circulating tumor cell (CTC) KW - dopamine transporter (DAT) KW - drug repositioning/repurposing KW - signal transducer and activator of transcription (STAT) KW - three-dimensional (3D) culture KW - tumoroids JF - Cancers JO - Cancers (Basel) VL - 12 IS - 2 N2 - Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. The properties of three-dimensional (3D) tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a 3D tumoroid-based screening system. We screened six pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with a matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and the properties of cancer stem cells/cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited the tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors. SN - 2072-6694 UR - https://www.unboundmedicine.com/medline/citation/32102440/Antiparkinson_Drug_Benztropine_Suppresses_Tumor_Growth,_Circulating_Tumor_Cells,_and_Metastasis_by_Acting_on_SLC6A3/DAT_and_Reducing_STAT3 L2 - http://www.mdpi.com/resolver?pii=cancers12020523 DB - PRIME DP - Unbound Medicine ER -
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