Culture-Based High Throughput Screen Detects Potent Anti-Ovarian Cancer Drugs

By LabMedica International staff writers
Posted on 24 Feb 2015

Cancer researchers have developed a high throughput system for screening drugs against ovarian tumors that is based on inhibition of cancer cells growing in a three-dimensional culture system.

Most high throughput screening (HTS) assays for drug discovery use cancer cells grown in monolayers despite the fact that the tumor microenvironment is known to contribute to cancer metastasis and drug resistance. To incorporate the tumor microenvironment into the drug screening process, investigators at the University of Chicago (IL, USA) coated the wells of 384- and 1,536-well microtiter plates with a multilayered cellular mixture containing primary human fibroblasts, mesothelial cells, and extracellular matrix. Cultures of fluorescently labeled ovarian cancer cells from three different lines (HeyA8, SKOV3ip1, and Tyk-nu) were added to the wells and then exposed to a library of small-molecule compounds. The numbers of adhering and invasive ovarian cancer cells were counted, and the inhibitory potential of each compound evaluated.

$Image: The micrograph shows a multilayered three-dimensional \"organotypic\" platform for quantitative high-throughput screening to identify new therapeutics for ovarian cancer. Fibroblasts are red. Mesothelial cells are blue. Ovarian cancer cells are green. The square image is the XY-planes (up-down, right-left). The images on the sides are Z-planes (depth) (Photo courtesy of Lengyel laboratory, University of Chicago).$

Image: The micrograph shows a multilayered three-dimensional \"organotypic\" platform for quantitative high-throughput screening to identify new therapeutics for ovarian cancer. Fibroblasts are red. Mesothelial cells are blue. Ovarian cancer cells are green. The square image is the XY-planes (up-down, right-left). The images on the sides are Z-planes (depth) (Photo courtesy of Lengyel laboratory, University of Chicago).

Results published in the February 5, 2015, online edition of the journal Nature Communications revealed that in the initial screen of 2,420 compounds there were 17 compounds that inhibited cell adhesion and invasion by at least 75%. Six of these compounds were active in a dose-response relationship in all three ovarian cancer cell lines, and four compounds significantly inhibited key ovarian cancer cell functions in the early steps of metastasis at low doses. One of the compounds, beta-escin, which is isolated from the seeds of the Chinese horse chestnut, was found to inhibit tumor growth and metastasis by 97%.

"Visualizing how cancer cells interact with a tumor microenvironment that accurately reflects the complex biology of ovarian cancer should help us understand the mechanisms underlying metastatic progression as well as identify new therapeutics that can inhibit this process," said senior author Dr. Ernst Lengyel, professor of obstetrics and gynecology at the University of Chicago. "We think this novel screening system has the potential to uncover new, more effective medications that could be targeted more specifically at a patient's cancer."

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