(S)-10-hydroxycamptothecin inhibits esophageal squamous cell carcinoma growth in vitro and in vivo via decreasing topoisomerase i enzyme activity

Mengqiu Song, Shuying Yin, Ran Zhao, Kangdong Liu, Joydeb Kumar Kundu, Jung Hyun Shim, Mee Hyun Lee, Zigang Dong

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7 Scopus citations

Abstract

Topoisomerase (TOP) I plays a major role in the process of supercoiled DNA relaxation, thereby facilitating DNA replication and cell cycle progression. The expression and enzymatic activity of TOP I is positively correlated with tumor progression. Although the anticancer activity of (S)-10-Hydroxycamptothecin (HCPT), a TOP I specific inhibitor, has been reported in various cancers, the effect of HCPT on esophageal cancer is yet to be examined. In this study, we investigate the potential of HCPT to inhibit the growth of ESCC cells in vitro and verify its anti-tumor activity in vivo by using a patient-derived xenograft (PDX) tumor model in mice. Our study revealed the overexpression of TOP I in ESCC cells and treatment with HCPT inhibited TOP I enzymatic activity at 24 h and decreased expression at 48 h and 72 h. HCPT also induced DNA damage by increasing the expression of H2A.XS139. HCPT significantly decreased the proliferation and anchorage-independent growth of ESCC cells (KYSE410, KYSE510, KYSE30, and KYSE450). Mechanistically, HCPT inhibited the G2/M phase cell cycle transition, decreased the expression of cyclin B1, and elevated p21 expression. In addition, HCPT stimulated ESCC cells apoptosis, which was associated with elevated expression of cleaved PARP, cleaved caspase-3, cleaved caspase-7, Bax, Bim, and inhibition of Bcl-2 expression. HCPT dramatically suppressed PDX tumor growth and decreased the expression of Ki-67 and TOP I and increased the level of cleaved caspase-3 and H2A.XS139 expression. Taken together, our data suggested that HCPT inhibited ESCC growth, arrested cell cycle progression, and induced apoptosis both in vitro and in vivo via decreasing the expression and activity of TOP I enzyme.

Original languageEnglish (US)
Article number1964
JournalCancers
Volume11
Issue number12
DOIs
StatePublished - Dec 2019

Bibliographical note

Funding Information:
1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; smq0705@126.com (M.S.); ysyyezi@163.com (S.Y.); zhaorpp1208@126.com (R.Z.); kangdongliu@126.com (K.L.) 2 China-US (Henan) Hormel Cancer Institute, No.127, Dongming Road, Jinshui District, Zhengzhou, Henan 450008, China 3 The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan 450001, China 4 Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, AB T6G 2R3, Canada; joydeb@ualberta.ca 5 Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Korea; s1004jh@gmail.com * Correspondence: zgdong@hci-cn.org (Z.D.); mhlee@hci-cn.org (M.-H.L.) or mhyun_lee@hanmail.net (M.-H.L.); Tel.: +86-371-6558-7008 (Z.D.); +86-371-6558-7008 (M.-H.L.); Fax.: +86-371-6558-7670 (Z.D.); +86-371-6558-7670 (M.-H.L.) † These authors contributed equally to this work.

Funding Information:
This work was supported by grant funding from the National Natural Science Foundation of China NSFC 81672767, NSFC 81972839, and the Key Program of Henan Province, China Grant NO.161100510300 and Henan Provincial Government, China.

Funding Information:
Funding: This work was supported by grant funding from the National Natural Science Foundation of China NSFC81672767, NSFC81972839, and the Key Program of Henan Province, China Grant NO.161100510300 and Henan Provincial Government, China.

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • (S)-10-Hydroxycamptothecin
  • Esophageal squamous cell carcinoma
  • Patient derived tumor xenograft (PDX)
  • Topoisomerase I

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