title: Novel 1, 3-N, O-Spiroheterocyclic compounds inhibit heparanase activity and enhance nedaplatin-induced cytotoxicity in cervical cancer cells.
abstract: 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.
authors.affiliation: The Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Song
authors.affiliation: The Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: The Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Qu
authors.affiliation: The Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Yunxiao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, China.
authors.forename: Jinchao
authors.initials: J
authors.lastname: Tao
authors.affiliation: The Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Zhengzhou University, Zhengzhou, 450014, China.
authors.forename: Jinquan
authors.initials: J
authors.lastname: Cui
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000099175:Heparanase
chemical_list: D000970:Antineoplastic Agents; D005966:Glucuronidase; D006571:Heterocyclic Compounds; D009944:Organoplatinum Compounds; D016271:Proto-Oncogene Proteins c-myc; D013141:Spiro Compounds; D019098:Telomerase; D016159:Tumor Suppressor Protein p53; D000099175:Heparanase; C489427:MYC protein, human; C053989:nedaplatin; C509186:TERT protein, human
keywords: 1,3-N,O-spiroheterocyclic; cervical carcinoma; heparanase; inhibitors