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Seno et al. Cancer Drug Resist 2019;2:335-50 Cancer
DOI: 10.20517/cdr.2019.01 Drug Resistance

Original Article Open Access

Daunorubicin can eliminate iPS-derived cancer stem
cells via ICAD/CAD-independent DNA fragmentation

Akimasa Seno , Akifumi Mizutani , Kazuki Aizawa , Ryoma Onoue , Junko Masuda , Naotaka Ochi ,
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Saki Taniguchi , Tatsuyuki Sota , Yuki Hiramoto , Taisuke Michiue , Neha Nair , Masaharu Seno 1,2
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1 Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems,
Okayama University, Okayama 700-8530, Japan.
2 Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama
700-8530, Japan.
Correspondence to: Prof. Masaharu Seno, Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and
Engineering in Health Systems, Okayama University, Bldg ENG-6, Room 460, 3-1-1 Tsushima-Naka, Kita, Okayama 700-8530,
Japan. E-mail: mseno@okayama-u.ac.jp
How to cite this article: Seno A, Mizutani A, Aizawa K, Onoue R, Masuda J, Ochi N, Taniguchi S, Sota T, Hiramoto Y, Michiue
T, Nair N, Seno M. Daunorubicin can eliminate iPS-derived cancer stem cells via ICAD/CAD-independent DNA fragmentation.
Cancer Drug Resist 2019;2:335-50. http://dx.doi.org/10.20517/cdr.2019.01
Received: 3 Jan 2019 First Decision: 11 Feb 2019 Revised: 20 Feb 2019 Accepted: 6 Mar 2019 Published: 19 Jun 2019

Science Editor: Aamir Ahmad Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu

Abstract
Aim: To identify a drug that can effectively eliminate these cancer stem cells (CSCs) and determine its mode of action.

Methods: CSCs were obtained from mouse induced pluripotent stem cells (miPSCs) using cancer cell-conditioned
media. Drug screening was performed on these cells or after transplantation into mice. Apoptosis was analyzed by flow
cytometry and western blotting.

Results: Drug screening studies showed that daunorubicin, a topoisomerase II inhibitor, is specifically cytotoxic to miPS-
CSCs. Daunorubicin-induced apoptosis was found to be associated with p53 accumulation, activation of the caspase
cascade, and oligonucleosomal DNA fragmentation. Treatment with the caspase inhibitor abolished daunorubicin-
induced DNA fragmentation and was therefore considered to act downstream of caspase activation. This was also
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suppressed by treatment with a Ca -specific chelator, which suggested that CAD endonuclease does not contribute.
Moreover, no obvious ICAD reduction/degradation was detected.

Conclusion: Daunorubicin effectively eliminated CSCs, which are dependent on the p53/caspase signaling cascade. The
current findings provided the basis for further studies on CSC-targeted drugs for the development of cancer treatment
strategies.
© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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