Quantitative Chemotherapeutic Profiling of Gynecologic Cancer Cell Lines Using Approved Drugs and Bioactive Compounds

Kirill Gorshkov,Ni Sima,Wei Sun,Billy Lu,Wei Huang,Jameson Travers,Carleen Klumpp-Thomas,Samuel G Michael,Tuan Xu,Ruili Huang,Emily M Lee,Xiaodong Cheng,Wei Zheng

doi:10.1016/j.tranon.2018.11.016

Abstract

Heterogeneous response to chemotherapy is a major issue for the treatment of cancer. For most gynecologic cancers including ovarian, cervical, and placental, the list of available small molecule therapies is relatively small compared to options for other cancers. While overall cancer mortality rates have decreased in the United States as early diagnoses and cancer therapies have become more effective, ovarian cancer still has low survival rates due to the lack of effective treatment options, drug resistance, and late diagnosis. To understand chemotherapeutic diversity in gynecologic cancers, we have screened 7914 approved drugs and bioactive compounds in 11 gynecologic cancer cell lines to profile their chemotherapeutic sensitivity. We identified two HDAC inhibitors, mocetinostat and entinostat, as pan-gynecologic cancer suppressors with IC50 values within an order of magnitude of their human plasma concentrations. In addition, many active compounds identified, including the non-anticancer drugs and other compounds, diversely inhibited the growth of three gynecologic cancer cell groups and individual cancer cell lines. These newly identified compounds are valuable for further studies of new therapeutics development, synergistic drug combinations, and new target identification for gynecologic cancers. The results also provide a rationale for the personalized chemotherapeutic testing of anticancer drugs in treatment of gynecologic cancer.

Highlights

The five main gynecologic cancers, including ovarian, cervical, uterine, vaginal, and vulvar, correspond to 12% (94,990) of new female cancer diagnoses annually in the United States [1]
While ovarian cancer is usually diagnosed at later stages of disease, resulting in a low 5-year survival of 29% for distant-stage disease, cervical cancer is typically diagnosed at early stages and has more favorable outcomes [2]
We have identified a group of non-anticancer compounds with antigynecologic cancer activities that can be further studied for target identification and drug development

Summary

Introduction

The five main gynecologic cancers, including ovarian, cervical, uterine, vaginal, and vulvar, correspond to 12% (94,990) of new female cancer diagnoses annually in the United States [1]. Uterine endometrial, ovarian, and cervical are the most prevalent, with ovarian being the fifth leading cause of death from cancer for females in the United States [2]. The high case-to-fatality ratio exhibited in ovarian cancer can be attributed to late-stage diagnosis, lack of effective drug therapies, and tumor heterogeneity. It is important to discover new therapeutics for ovarian cancers that can improve survival in latestage ovarian cancer patients. While ovarian cancer is usually diagnosed at later stages of disease, resulting in a low 5-year survival of 29% for distant-stage disease, cervical cancer is typically diagnosed at early stages and has more favorable outcomes [2].

Methods

Results

Conclusion