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Development of a Rapid In Vitro Screening Assay Using Metabolic Inhibitors to Detect Highly Selective Anticancer
Felagot A Abebe1, Megan D Hopkins1, Suraj N Vodnala1
1Department of Chemistry and Biochemistry, The University of Tulsa, 800 South Tucker Drive, Tulsa, Oklahoma 74104, United States.
Abstract:
Traditional long exposure (24-72 h) cell viability assays for identification of potential drug compounds can fail to identify compounds that are: (a) biologically active but not toxic and (b) inactive without the addition of a synergistic additive. Herein, we report the development of a rapid (1-2 h) compound screening technique using a commercially available cell viability kit (CellTiter-Glo) that has led to the detection of compounds that were not identified as active agents using traditional cytotoxicity screening methods. These compounds, in combination with metabolic inhibitor 2-deoxyglucose, display selectivity toward a pancreatic cancer cell line. An evaluation of 11 mammalian cell lines against 30 novel compounds and two metabolic inhibitors is reported. The inclusion of metabolic inhibitors during an initial screening process, and not simply during mechanistic investigations of a previously identified hit compound, provides a rapid and sensitive tool for identifying drug candidates potentially overlooked by other methods.
Insights
This study introduces a rapid cell viability assay for drug discovery. The new method identifies compounds missed by traditional assays, especially when combined with metabolic inhibitors for pancreatic cancer treatment.
Area of Science:
- Pharmacology
- Drug Discovery
- Cancer Research
Background:
- Traditional cell viability assays (24-72h) miss compounds active without toxicity or requiring synergistic additives.
- Existing methods may overlook potential drug candidates due to limitations in screening duration and compound interaction detection.
Purpose of the Study:
- To develop a rapid (1-2h) cell viability screening technique for identifying novel drug compounds.
- To detect compounds missed by traditional cytotoxicity screening, particularly those effective with synergistic additives.
- To evaluate the efficacy of novel compounds and metabolic inhibitors in various cancer cell lines.
Main Methods:
- Utilized a commercially available cell viability kit (CellTiter-Glo) for rapid screening.
- Screened 30 novel compounds and two metabolic inhibitors across 11 mammalian cell lines.
- Incorporated metabolic inhibitors (e.g., 2-deoxyglucose) during the initial screening phase.
Main Results:
- Identified compounds not detected by traditional cytotoxicity screening methods.
- Observed selective activity of certain compounds in combination with 2-deoxyglucose against a pancreatic cancer cell line.
- Demonstrated the effectiveness of the rapid assay in identifying potential drug candidates.
Conclusions:
- The rapid (1-2h) assay is a sensitive tool for drug candidate identification.
- Including metabolic inhibitors in initial screening enhances the detection of overlooked drug candidates.
- This approach offers a valuable alternative to traditional methods for drug discovery, especially in oncology.
