(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

doi:10.3390/cancers11121964

(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

The Hormel Institute

Research output: Contribution to journal › Article › peer-review

16 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.X^S139. 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.X^S139 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 language	English (US)
Article number	1964
Journal	Cancers
Volume	11
Issue number	12
DOIs	https://doi.org/10.3390/cancers11121964
State	Published - Dec 2019

Bibliographical note

Funding Information:
1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; [email protected] (M.S.); [email protected] (S.Y.); [email protected] (R.Z.); [email protected] (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; [email protected] 5 Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Korea; [email protected] * Correspondence: [email protected] (Z.D.); [email protected] (M.-H.L.) or [email protected] (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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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers11121964

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@article{757845cb224d4851ac084723bedf4ed6,

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

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.",

keywords = "(S)-10-Hydroxycamptothecin, Esophageal squamous cell carcinoma, Patient derived tumor xenograft (PDX), Topoisomerase I",

author = "Mengqiu Song and Shuying Yin and Ran Zhao and Kangdong Liu and Kundu, {Joydeb Kumar} and Shim, {Jung Hyun} and Lee, {Mee Hyun} and Zigang Dong",

note = "Funding Information: 1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; [email protected] (M.S.); [email protected] (S.Y.); [email protected] (R.Z.); [email protected] (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; [email protected] 5 Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Korea; [email protected] * Correspondence: [email protected] (Z.D.); [email protected] (M.-H.L.) or [email protected] (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: {\textcopyright} 2019 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2019",

month = dec,

doi = "10.3390/cancers11121964",

language = "English (US)",

volume = "11",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "12",

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T1 - (S)-10-hydroxycamptothecin inhibits esophageal squamous cell carcinoma growth in vitro and in vivo via decreasing topoisomerase i enzyme activity

AU - Song, Mengqiu

AU - Yin, Shuying

AU - Zhao, Ran

AU - Liu, Kangdong

AU - Kundu, Joydeb Kumar

AU - Shim, Jung Hyun

AU - Lee, Mee Hyun

AU - Dong, Zigang

N1 - Funding Information: 1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China; [email protected] (M.S.); [email protected] (S.Y.); [email protected] (R.Z.); [email protected] (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; [email protected] 5 Department of Pharmacy, College of Pharmacy, Mokpo National University, Jeonnam 58554, Korea; [email protected] * Correspondence: [email protected] (Z.D.); [email protected] (M.-H.L.) or [email protected] (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.

PY - 2019/12

Y1 - 2019/12

N2 - 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.

AB - 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.

KW - (S)-10-Hydroxycamptothecin

KW - Esophageal squamous cell carcinoma

KW - Patient derived tumor xenograft (PDX)

KW - Topoisomerase I

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U2 - 10.3390/cancers11121964

DO - 10.3390/cancers11121964

M3 - Article

C2 - 31817790

AN - SCOPUS:85076209309

SN - 2072-6694

VL - 11

JO - Cancers

JF - Cancers

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M1 - 1964

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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