Acetaminophen-induced differentiation of human breast cancer stem cells and inhibition of tumor xenograft growth in mice

Masaya Takehara, Tatsuya Hoshino, Takushi Namba, Naoki Yamakawa, Tohru Mizushima

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

It is now believed that cancer stem cells (CSCs) that are resistant to chemotherapy due to their undifferentiated nature drive tumor growth, metastasis and relapse, so development of drugs that induce differentiation of CSCs should have a profound impact on cancer eradication. In this study, we screened medicines that are already in clinical use for drugs that induce differentiation of CSCs. We used MDA-MB-231, a human breast cancer cell line that contains cancer stem cell-like cells. We found that acetaminophen, an anti-inflammatory, antipyretic and analgesic drug, induces differentiation of MDA-MB-231 cells. Differentiation was assessed by observing alterations in cell shape and expression of differentiated and undifferentiated cell markers, a decrease in cell invasion activity and an increase in susceptibility to anti-tumor drugs. This increased susceptibility seems to involve suppression of expression of multidrug efflux pumps. We also suggest that this induction of differentiation is mediated by inhibition of a Wnt/β-catenin canonical signaling pathway. Treatment of MDA-MB-231 cells with acetaminophen in vitro resulted in the loss of their tumorigenic ability in nude mice. Furthermore, administration of acetaminophen inhibited the growth of tumor xenografts of MDA-MB-231 cells in both the presence and absence of simultaneous administration of doxorubicine, a typical anti-tumor drug for breast cancer. Analysis with various acetaminophen derivatives revealed that o-acetamidophenol has a similar differentiation- inducing activity and a similar inhibitory effect on tumor xenograft growth. These results suggest that acetaminophen may be beneficial for breast cancer chemotherapy by inducing the differentiation of CSCs.

Original languageEnglish
Pages (from-to)1124-1135
Number of pages12
JournalBiochemical Pharmacology
Volume81
Issue number9
DOIs
Publication statusPublished - 2011 May 1
Externally publishedYes

Fingerprint

Neoplastic Stem Cells
Acetaminophen
Stem cells
Heterografts
Tumors
Breast Neoplasms
Growth
Neoplasms
Chemotherapy
Pharmaceutical Preparations
Drug Therapy
Catenins
Antipyretics
Cell Shape
Non-Steroidal Anti-Inflammatory Agents
Nude Mice
Medicine
Analgesics
Anti-Inflammatory Agents
Cells

Keywords

  • Acetaminophen
  • Anti-cancer drug
  • Cancer stem cells
  • Differentiation

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Acetaminophen-induced differentiation of human breast cancer stem cells and inhibition of tumor xenograft growth in mice. / Takehara, Masaya; Hoshino, Tatsuya; Namba, Takushi; Yamakawa, Naoki; Mizushima, Tohru.

In: Biochemical Pharmacology, Vol. 81, No. 9, 01.05.2011, p. 1124-1135.

Research output: Contribution to journalArticle

Takehara, Masaya ; Hoshino, Tatsuya ; Namba, Takushi ; Yamakawa, Naoki ; Mizushima, Tohru. / Acetaminophen-induced differentiation of human breast cancer stem cells and inhibition of tumor xenograft growth in mice. In: Biochemical Pharmacology. 2011 ; Vol. 81, No. 9. pp. 1124-1135.
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