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Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Screening-based approach to discover effective platinum-based chemotherapies for cancers with poor prognosis
Hristo P Varbanov1, Fabien Kuttler2, Damiano Banfi2
1Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Abstract:
Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput screening assay for identification of synergistic combinations between broadly applied platinum-based chemotherapeutics and drugs from a library composed of 1280 chemically and pharmacologically diverse (mostly FDA approved) compounds. The assay was performed on chemoresistant cell lines derived from lung (A549) and pancreatic (PANC-1) carcinoma, where platinum-based combination regimens are currently applied though with limited success. The synergistic combinations identified during the screening were validated by synergy quantification using the combination index method and via high content fluorescent microscopy analysis. New promising synergistic combinations discovered using this approach include compounds currently not used as anticancer drugs, such as cisplatin or carboplatin with hycanthone and cisplatin with spironolactone in pancreatic carcinoma, and carboplatin and deferoxamine in non-small cell lung cancer. Strong synergy between cisplatin or carboplatin and topotecan in PANC-1 cells, compared to A549 cells, suggests that this combination, currently used in lung cancer treatment regimens, could be applied to pancreatic carcinoma as well. Several drugs used to treat diseases other than cancer, including pyrvinium pamoate, auranofin, terfenadine and haloprogin, showed strong cytotoxicity on their own and synergistic interactions with platinum drugs. This study demonstrates that non-obvious drug combinations that would not be selected based on complementary mechanisms can be identified via high-throughput screening.
Insights
High-throughput screening identified novel synergistic drug combinations for cancer therapy. This approach uncovered non-obvious platinum-based chemotherapy pairings, including drugs not typically used for cancer treatment, offering new treatment avenues.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Cancer treatment often relies on drug combinations selected for complementary mechanisms.
- Platinum-based chemotherapeutics are widely used but have limited success in chemoresistant lung and pancreatic cancers.
- Novel strategies are needed to identify effective drug combinations for difficult-to-treat cancers.
Purpose of the Study:
- To develop and implement a high-throughput screening assay for identifying synergistic drug combinations involving platinum-based chemotherapeutics.
- To discover novel, non-obvious drug combinations for chemoresistant lung and pancreatic cancer cell lines.
- To validate identified synergistic combinations using established quantitative methods.
Main Methods:
- A cell-based high-throughput screening assay was utilized.
- The assay screened 1280 diverse compounds in combination with platinum-based drugs (cisplatin, carboplatin).
- Screening was performed on chemoresistant lung (A549) and pancreatic (PANC-1) carcinoma cell lines, with validation via combination index and high-content fluorescent microscopy.
Main Results:
- Several novel synergistic combinations were identified, including cisplatin/carboplatin with hycanthone, cisplatin with spironolactone, and carboplatin with deferoxamine.
- Strong synergy was observed between cisplatin/carboplatin and topotecan in PANC-1 cells, suggesting potential for pancreatic cancer treatment.
- Drugs not typically used as anticancer agents, such as pyrvinium pamoate, auranofin, terfenadine, and haloprogin, demonstrated significant cytotoxicity and synergistic interactions with platinum drugs.
Conclusions:
- High-throughput screening can identify synergistic drug combinations that would not be predicted by complementary mechanisms.
- This approach reveals promising new therapeutic combinations for chemoresistant lung and pancreatic cancers.
- The study highlights the potential of repurposing non-anticancer drugs and identifying novel platinum-based drug pairings for improved cancer therapy.
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