Oncotarget

Research Papers:

Repositioning CEP-1347, a chemical agent originally developed for the treatment of Parkinson’s disease, as an anti-cancer stem cell drug

Masashi Okada, Hiroyuki Takeda, Hirotsugu Sakaki, Kenta Kuramoto, Shuhei Suzuki, Tomomi Sanomachi, Keita Togashi, Shizuka Seino and Chifumi Kitanaka _

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Oncotarget. 2017; 8:94872-94882. https://doi.org/10.18632/oncotarget.22033

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Abstract

Masashi Okada1, Hiroyuki Takeda1,2, Hirotsugu Sakaki1,3, Kenta Kuramoto1, Shuhei Suzuki1,2, Tomomi Sanomachi1,2, Keita Togashi1,4, Shizuka Seino1,5 and Chifumi Kitanaka1,5

1Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan

2Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata 990-9585, Japan

3Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata 990-9585, Japan

4Department of Ophthalmology, Yamagata University School of Medicine, Yamagata 990-9585, Japan

5Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan

Correspondence to:

Chifumi Kitanaka, email: ckitanak@med.id.yamagata-u.ac.jp

Masashi Okada, email: m-okada@med.id.yamagata-u.ac.jp

Keywords: mixed lineage kinase (MLK); c-Jun N-terminal kinase (JNK); serial transplantation assay; xenograft; brain tumor

Received: August 09, 2017     Accepted: September 22, 2017     Published: October 24, 2017

ABSTRACT

CEP-1347 is a mixed lineage kinase inhibitor tested in a large-scale phase 2/3 clinical trial in early Parkinson’s disease, in which its safety and tolerability, but nevertheless not efficacy, was demonstrated. Here we identify by drug repositioning CEP-1347 as a potential anti-cancer stem cell drug. In vitro, CEP-1347 efficiently induced differentiation and inhibited the self-renewal and tumor-initiating capacities of human cancer stem cells from glioblastoma as well as from pancreatic and ovarian cancers at clinically-relevant concentrations, without impairing the viability of normal fibroblasts and neural stem cells. In vivo, a 10-day systemic administration of CEP-1347 at a dose that was less than 1/10 the mouse equivalent of the dose safely given to humans for 2 years was sufficient to effectively reduce tumor-initiating cancer stem cells within established tumors in mice. Furthermore, the same treatment protocol significantly extended the survival of mice receiving orthotopic implantation of glioma stem cells. Together, our findings suggest that CEP-1347 is a promising candidate for cancer stem cell-targeting therapy and that further clinical and preclinical studies are warranted to evaluate its efficacy in cancer treatment.


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