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Demethoxycurcumin was superior to temozolomide in the inhibition of the growth of glioblastoma stem cells in vivo

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Tumor Biology

Abstract

Temozolomide (TMZ) is widely used in the treatment of glioblastoma multiforme (GBM) as it can effectively inhibit the growth of GBM for some months; however, this cancer type is still incurable. The existence of glioma stem cells (GSCs) is thought to be responsible for the invariable recurrence of GBM after treatment, but GSCs are insensitive to TMZ. Our recent research showed that demethoxycurcumin (DMC), a component of curcumin, was superior to TMZ in its ability to inhibit proliferation and induce apoptosis of GSCs in vitro. In addition, the combined treatment of TMZ + DMC induced more obvious anti-GSC effects. However, in this study, no obvious synergistic anti-GSC effects of TMZ + DMC were found in vivo, while DMC was still superior to TMZ with respect to growth inhibition of GSCs in vivo. Furthermore, immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed that such inhibitory effects were mainly related to the inhibition of cell proliferation rather than to apoptosis. However, a high concentration of DMC (50 mg/kg) alone or combined with TMZ could also induce approximately 10 % of the cells to undergo apoptosis according to a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Finally, an investigation of the underlying mechanism revealed that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) 3 signaling pathway played an important role in the anti-GSC effects. When the JAK inhibitor AG490 was applied, the anti-GSC effects of DMC were enhanced. Taken together, the present work reveals that DMC is superior to TMZ with respect to its anti-GSC effects in vivo, which are mediated through the inhibition of the activation of the JAK/STAT3 pathway; however, DMC demonstrated no synergistic effects with TMZ.

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Abbreviations

TMZ:

Temozolomide

DMC:

Demethoxycurcumin

GSCs:

Glioma stem cells

GBM:

Glioblastoma multiforme

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Acknowledgments

This work was supported by the China Natural Science Foundation (81000963, 81370062, 81302196, and 31470853), Jiangsu Province’s 333 Talent Program (BRA2011046), Jiangsu Province “six personnel peak” funded projects (2013-WSN-145/028), Jiangsu Province’s Natural Science Foundation (BK2012670), Medical Research Foundation by Jiangsu Province Health Department (YG201301 and Z201318), the Clinical Technology Development of Jiangsu University (JLY20120053), the Kunshan Social Development Foundation (KS1006, KS1009), and the Suzhou Social Development Foundation (SYS201063). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Department of Neurosurgery, Liyang People’s Hospital Affiliated to Nantong University, Liyang, 213300, China

    Liang Leng & Xiaojun Zhong

  2. Department of Neurosurgery, Fourth Affiliated Yancheng Hospital of Nantong University, Yancheng, 224000, China

    Guan Sun

  3. Department of Immunology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China

    Wen Qiu

  4. Department of Neurosurgery, The First People’s Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, 215300, China

    Lei Shi

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  1. Liang Leng
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  2. Xiaojun Zhong
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  3. Guan Sun
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  4. Wen Qiu
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  5. Lei Shi
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Corresponding authors

Correspondence to Wen Qiu or Lei Shi.

Ethics declarations

This study was approved by the ethics committee of the hospital, and informed consent forms were signed by the family members of the patients. All procedures were conducted in accordance with the animal care laws of the First People’s Hospital of Kunshan affiliated with Jiangsu University.

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None

Additional information

Liang Leng, Xiaojun Zhong, Guan Sun, and Lei Shi contributed equally to this work.

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Leng, L., Zhong, X., Sun, G. et al. Demethoxycurcumin was superior to temozolomide in the inhibition of the growth of glioblastoma stem cells in vivo. Tumor Biol. 37, 15847–15857 (2016). https://doi.org/10.1007/s13277-016-5399-x

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  • DOI: https://doi.org/10.1007/s13277-016-5399-x

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