Abstract
DNA topoisomerase I (TOP1) levels of several human neoplasms are higher than those of normal tissues. TOP1 inhibitors are widely used in treating conventional therapy-resistant ovarian cancers. However, patients may develop resistance to TOP1 inhibitors, hampering chemotherapy success. In this study, we examined the mechanisms associated with the development of camptothecin (CPT) resistance in ovarian cancers and identified evodiamine (EVO), a natural product with TOP1 inhibiting activity that overcomes the resistance. The correlations among TOP1 levels, cancer staging, and overall survival (OS) were analyzed. The effect of EVO on CPT-resistant ovarian cancer was evaluated in vitro and in vivo. TOP1 was associated with poor prognosis in ovarian cancers (p = 0.024). EVO induced apoptosis that was detected using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The tumor size decreased significantly in the EVO treatment group compared with the control group (p < 0.01) in a xenograft mouse model. Effects of drugs targeting TOP1 for prognosis and therapy in CPT-resistant ovarian cancer are anticipated. EVO with TOP1 can be developed as an antiproliferative agent for overcoming CPT resistance in ovarian cancers.
Highlights
Ovarian cancer has no specific signs or symptoms and is usually diagnosed at an advanced stage, making it the most lethal gynecological cancer in the Western world [1]
We investigated the relationship between TOP1 expression levels and the overall survival (OS), defined as patients with a ovarian cancer can die directly from this disease or from an unrelated cause
We examined the contribution of the TOP1 mRNA expression to the OS of ovarian cancer patients using the KM plotter, which assessed the effect of 22,277 genes on the survival of 1,464 ovarian cancer patients
Summary
Ovarian cancer has no specific signs or symptoms and is usually diagnosed at an advanced stage, making it the most lethal gynecological cancer in the Western world [1]. Standard chemotherapy for ovarian cancer is frequently accompanied by chemoresistance, which is a major. Stochastic mutations caused by selection pressure, sequential genetic changes induced by specialized stroma, and stemness of cancer cells were proposed to explain the survival of chemoresistant cells during chemotherapy [3]. Notch pathway and DNA topoisomerase I (TOP1) inhibitors have been widely used in cisplatin-resistant ovarian cancers [5]. Patients can develop TOP1 inhibitor resistance, hampering the success of therapy [6]. Use of combination therapy over single-agent chemotherapy leads to improved outcomes in ovarian cancer [7]. Chemotherapy-induced side effects are alleviated after using natural products such as polyphyllin D [8], emodin [9] or Rosa Roxburghii Tratt [10] whereas antitumor activity and immunomodulatory functions are observed [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
