CKD-602, a topoisomerase I inhibitor, induces apoptosis and cell-cycle arrest and inhibits invasion in cervical cancer

Sungha Lee,Minji Ko,Hyewon Lee,Seon Ui Lee,Jing Jing Liu,Jae Young Park,Jung Yoon Ho,Minwha Baik,Youn Jin Choi,Soo Young Hur

doi:10.1186/s10020-019-0089-y

Abstract

BackgroundCervical cancer is the third most common gynecological malignancy. Conventional treatment options are known to be ineffective for the majority of patients with advanced or recurrent cervical cancer. Therefore, novel therapeutic agents for cervical cancer are necessary. In this study, the effects of CKD-602 in cervical cancer were investigated.MethodsThree established human, immortalized, cervical cancer cell lines (CaSki, HeLa and SiHa) were used in this study. Following treatment with CKD-602, apoptosis was quantified using fluorescein isothiocyanate Annexin V-FITC and propidium iodide (PI) detection kit and cell cycle analysis was analyzed using fluorescence activated cell sorting (FACS). Transwell chambers were used for invasion assays. Western blot assay was performed to analyze proteomics. CaSki cells were subcutaneously injected into BALB/c-nude mice and cervical cancer xenograft model was established to elucidate the antitumor effect of CKD-602 in vivo.ResultsTreatment with CKD-602 induced apoptosis and increased expression of the enzyme PARP, cleaved PARP, and BAX. In addition, expression of phosphorylated p53 increased. Cell cycle arrest at G2/M phase and inhibition of invasion were detected after treatment with CKD-602. A significant decrease in cervical cancer tumor volume was observed in this in vivo model, following treatment with CKD-602.ConclusionsThis is the first report of CKD-602 having an antitumor effect in cervical cancer in both an in vitro and in vivo models. The results of this study indicate that CKD-602 may be a novel potential drug, targeting cervical cancer, providing new opportunities in the development of new therapeutic strategies.

Highlights

Cervical cancer is the third most common gynecological malignancy
All three cell lines were integrated with high-risk Human papillomavirus (HPV); CaSki and Siha cell lines were integrated with HPV-16 and the HeLa cell line was integrated with HPV-18
Previous studies have demonstrated that CKD-602, a topoisomerase I (TOP1) inhibitor, is effective in the treatment of various cancers such as small cell lung carcinoma, oral squamous cell carcinoma and glioblastoma (Kim et al, 2013; Kim et al, 2015; Lee et al, 1998)

Summary

Introduction

Cervical cancer is the third most common gynecological malignancy. Conventional treatment options are known to be ineffective for the majority of patients with advanced or recurrent cervical cancer. Cervical cancer is the third most common gynecological malignancy and is responsible for 10–15% of cancer-related death in women (Jemal et al, 2011). Conventional treatment options (e.g., chemotherapy, radiation and surgical resection) are known to be ineffective for the majority of patients with advanced or recurrent cervical cancer, highlighting the need to identify novel treatment agents (Smith et al, 1993). Topoisomerase I (TOP1) cuts one strand in the double-stranded DNA, independent of ATP. Topoisomerase II (TOP2) cuts both strands in DNA and is dependent on ATP for its activity (Xu and Her, 2015). Camptothecin (CPT) is the TOP1 inhibitor which was originally isolated from the Chinese tree Camptotheca acuminate, it is no longer in use due to detrimental side

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