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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.

SUBMITTER: Gorshkov K

PROVIDER: S-EPMC6302136 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Gorshkov Kirill K Sima Ni N Sun Wei W Lu Billy B Huang Wei W Travers Jameson J Klumpp-Thomas Carleen C Michael Samuel G SG Xu Tuan T Huang Ruili R Lee Emily M EM Cheng Xiaodong X Zheng Wei W

Translational oncology 20181218 3

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, dru ...[more]

PMID: 30576957

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Project description:The most effective way to move from target identification to the clinic is to identify already approved drugs with the potential for activating or inhibiting unintended targets (repurposing or repositioning). This is usually achieved by high throughput chemical screening, transcriptome matching, or simple in silico ligand docking. We now describe a novel rapid computational proteochemometric method called "train, match, fit, streamline" (TMFS) to map new drug-target interaction space and predict new uses. The TMFS method combines shape, topology, and chemical signatures, including docking score and functional contact points of the ligand, to predict potential drug-target interactions with remarkable accuracy. Using the TMFS method, we performed extensive molecular fit computations on 3671 FDA approved drugs across 2335 human protein crystal structures. The TMFS method predicts drug-target associations with 91% accuracy for the majority of drugs. Over 58% of the known best ligands for each target were correctly predicted as top ranked, followed by 66%, 76%, 84%, and 91% for agents ranked in the top 10, 20, 30, and 40, respectively, out of all 3671 drugs. Drugs ranked in the top 1-40 that have not been experimentally validated for a particular target now become candidates for repositioning. Furthermore, we used the TMFS method to discover that mebendazole, an antiparasitic with recently discovered and unexpected anticancer properties, has the structural potential to inhibit VEGFR2. We confirmed experimentally that mebendazole inhibits VEGFR2 kinase activity and angiogenesis at doses comparable with its known effects on hookworm. TMFS also predicted, and was confirmed with surface plasmon resonance, that dimethyl celecoxib and the anti-inflammatory agent celecoxib can bind cadherin-11, an adhesion molecule important in rheumatoid arthritis and poor prognosis malignancies for which no targeted therapies exist. We anticipate that expanding our TMFS method to the >27 000 clinically active agents available worldwide across all targets will be most useful in the repositioning of existing drugs for new therapeutic targets.

Dataset Information

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

Publications

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

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