Research Papers:

Novel 1, 3-N, O-Spiroheterocyclic compounds inhibit heparanase activity and enhance nedaplatin-induced cytotoxicity in cervical cancer cells

Yanan Song, Bin Hu, Hongjie Qu, Lu Wang, Yunxiao Zhang, Jinchao Tao and Jinquan Cui _

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Oncotarget. 2016; 7:36154-36167. https://doi.org/10.18632/oncotarget.8959

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Yanan Song1,*, Bin Hu1,*, Hongjie Qu1, Lu Wang1, Yunxiao Zhang2, Jinchao Tao2, Jinquan Cui1

1The Department of Obstetrics and Gynecology, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China

2The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, China

*These authors contributed equally to this work

Correspondence to:

Jinquan Cui, email: [email protected]

Keywords: cervical carcinoma, heparanase, inhibitors, 1,3-N,O-spiroheterocyclic

Received: January 19, 2016     Accepted: March 31, 2016     Published: April 23, 2016


Heparanase (HPA) is an enzyme that plays an important role in cancer metastasis and angiogenesis and is a potential target for molecular treatment of tumors. We previously found that abnormally high HPA expression in cervical cancer tissues is associated with poor survival and increased lymph node metastasis. The present study was conducted to assess the utility of inhibiting HPA enzyme activity in cervical cancer treatment. Two series of 13 novel HPA inhibitors were synthesized and optimized. All tested inhibitors reduced HPA enzyme activity (IC50 values ranged from 4.47 μM to 47.19 μM) and inhibited the growth of HeLa cells (IC50 values ranged from 48.16 μM to 96.64 μM). The No. 16 inhibitor inhibited the migration and growth of HeLa and Siha cells in a dose- and time-dependent manner, and increased cell apoptosis and cell cycle G0/G1 and G2/M phase arrest, while decreasing the S phase cell population. More importantly, No. 16 sensitized cervical cancer cells to low concentrations of nedaplatin, decreased HPA, c-Myc and h-TERT levels, and increased p53 levels in HeLa and Siha cells. These results suggest that this HPA inhibitor reduced proliferation and HPA expression in cervical cancer cells by restoring p53 activity and downregulating h-TERT and c-Myc expression.

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