Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3 and Reducing STAT3

Chiharu Sogawa
ORCID logo ,
Manh Tien Tran
,
Masayuki Ishige
,
Kilian Trin
,
Yuka Okusha
,
Eman Ahmed Taha
,
Yanyin Lu
,
Hotaka Kawai
,
Norio Sogawa
,
Masaharu Takigawa
,
Stuart K. Calderwood
,
Kuniaki Okamoto
,
Ken-ichi Kozaki
,
Takanori Eguchi
*
Version 1 : Received: 3 February 2020 / Approved: 3 February 2020 / Online: 3 February 2020 (03:16:54 CET)

A peer-reviewed article of this Preprint also exists.

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. Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3. Cancers 2020, 12, 523. 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. Antiparkinson Drug Benztropine Suppresses Tumor Growth, Circulating Tumor Cells, and Metastasis by Acting on SLC6A3/DAT and Reducing STAT3. Cancers 2020, 12, 523.

Abstract

Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. Properties of three-dimensional 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 tumoroid-based screening system. We screened 6 pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The effects of one of the hit compounds were examined on tumor formation and progression in vitro and in vivo. 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 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 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.

Keywords

drug repositioning/repurposing; dopamine transporter (DAT); benztropine; tumoroids; signal transducer and activator of transcription (STAT); circulating tumor cells (CTC); three-dimensional (3D) culture

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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