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  • [J Cancer Res Clin Oncol.] Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

    [J Cancer Res Clin Oncol.] Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

    연세대 / 오형철, 육종인*, 강석구*

  • 출처
    J Cancer Res Clin Oncol.
  • 등재일
    2020 Jul 25. doi: 10.1007/s00432-020-03330-7. O
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    Abstract
    Purpose: Glioblastoma (GBM) is the most aggressive type of brain tumor and has poor survival outcomes, even after a combination of surgery, radiotherapy, and chemotherapy. Temozolomide is the only agent that has been shown to be effective against GBM, suggesting that combination of temozolomide with other agents may be more effective. Niclosamide, an FDA approved anthelmintic agent, has shown anti-cancer effects against human colon, breast, prostate cancers as well as GBM. However, the efficacy of the combination of niclosamide with temozolomide against GBM tumorspheres (TSs) has not been determined. We hypothesized that the combined treatment could effectively suppress GBM TSs.

    Methods: GBM TSs (TS15-88, GSC11) were treated with niclosamide and/or temozolomide. Combined effects of two drugs were evaluated by measuring viability, neurosphere formation, and 3D-invasion in collagen matrix. Transcriptional profiles of GBM TS were analyzed using RNA sequencing. In vivo anticancer efficacy of combined drugs was tested in a mouse orthotopic xenograft model.

    Results: Combination treatment of niclosamide and temozolomide significantly inhibited the cell viability, stemness, and invasive properties of GBM TSs. This combined treatment significantly down-regulated the expression of epithelial mesenchymal transition-related markers, Zeb1, N-cadherin, and β-catenin. The combined treatment also significantly decreased tumor growth in orthotopic xenograft models.

    Conclusion: The combination of niclosamide and temozolomide effectively decreased the stemness and invasive properties of GBM TSs, suggesting that this regimen may be therapeutically effective in treating patients with GBM.

     

     

     

     

    Affiliations

    Hyeong-Cheol Oh  1 , Jin-Kyoung Shim  1 , Junseong Park  1 , Ji-Hyun Lee  1 , Ran Joo Choi  1 , Nam Hee Kim  2 , Hyun Sil Kim  2 , Ju Hyung Moon  1 , Eui Hyun Kim  1 , Jong Hee Chang  1 , Jong In Yook  3 , Seok-Gu Kang  4   5
    1 Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
    2 Department of Oral Pathology, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
    3 Department of Oral Pathology, Yonsei University College of Dentistry, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. jiyook@yuhs.ac.
    4 Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. seokgu9@gmail.com.
    5 Department of Medical Science, Yonsei University Graduate School, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. seokgu9@gmail.com.

  • 키워드
    Glioblastoma; Invasion; Niclosamide; Temozolomide; Tumorsphere.
  • 연구소개
    본 연구는 기생충 약으로 알려진 niclosamide의 glioblastoma (GBM) tumorsphere (TS)에 대한 anticancer effect 및 대표적인 GBM 항암제인 temozolomide와의 병합 효과를 규명하였습니다. niclosamide, temozolomide 병합요법이 GBM TS cell viabiltiy를 떨어뜨리고, epithelial mesenchymal transition (EMT) 발현을 감소시킴으로써 GBM invasiveness를 억제한다는 것을 밝혔습니다. 또한, 병합요법이 GBM stemness property를 억제하고, animal model을 통해 생존율을 유의미하게 증가시킨다는 것을 보였습니다. RNA sequencing을 통해 병합요법이 Stemness, EMT를 encoding하는 유전자의 발현을 억제한다는 것을 확인 하였습니다. 더 나아가, niclosamide는 STAT3 pathway에서 phosphporylated STAT3의 발현을 억제하고 이에 따라 MGMT 또한 감소시킴을 western blotting을 통해 밝히면서 temozolomide resistant GBM에서 niclosamide 병합요법이 효과적인 치료 대안이 될 수도 있음을 소개하였습니다.
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