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

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.

Targeting the JAK/STAT pathway in solid tumors

“…Two studies showed that fedratinib in combination with erlotinib (EGFR tyrosine kinase inhibitor) decreased STAT3 activation and increased apoptosis in erlotinib-resistant NSCLC cells and inhibited tumor growth in in vivo murine models [155,156] . This agent has also demonstrated cell-killing activity against ovarian and cervical cancer cells [157] . Fedratinib inhibited mammosphere formation and in combination with carboplatin, inhibited breast cancer tumor growth in mice [158] .…”

Copper Coordination Compounds as Biologically Active Agents

“…Ultimately, coordination of copper with the elesclomol ligand disrupts the production and metabolism of cellular energy and triggers the path of mitochondrial apoptosis in tumor cells, leading to their death [44]. An antitumor activity of the redox-active copper coordination compound was also confirmed in [45], where the potential effectiveness of elesclomol in treating ovarian cancer was shown. The elesclomol ligand showed antiproliferative activity on six cell lines of gynecological cancer with an IC50 of 0.173 µ M and an IC90 of 0.283 µ M (tests were performed with Cu-preincubated cell lines).…”

Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

“…Entinostat (15) Inhibition of HDACs 1, 2, 3, and 9 Entinostat presented anti-proliferative activity in vitro and in vivo against several cancer lines, including cervical cancer and a panel of gynecologic cell lines. (Saito et al, 1999;Lauffer et al, 2013;Gorshkov et al, 2019) HDAC1 19) presented an activity against HeLa cells and IC 50 value of 0.92 mM and increased intracellular levels of ROS after treatment with a concentration of 0.8 mM. (Oca et al, 2018;Sixto-López et al, 2020) HDAC1:153.78 µM HDAC6:>1000 µM HDAC8:>1000 µM Luotonin A derivative (20) Inhibition of HDAC 1 and 2 Compound (20) presented an antiproliferative activity against HeLa cells identical to Luotonin A, its precursor; however, the selective index was 4.4 times superior for the synthesized compound compared to Luotonin A.…”