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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin
Svetlana Paskas1, Philipp Stockmann2, Sanja Mijatović1
1Department of Immunology, Institute for Biological Research "Siniša Stanković", National Institute of Republic of Serbia, Belgrade University, 11060 Belgrade, Serbia.
Abstract:
The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug resistance, has the ability to transport a broad spectrum of substrates out of the cell and is, therefore, considered as a potential target to improve cancer therapies or as an approach to combat drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein (BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently, with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa, DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480 cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly, co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However, a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition by the carborane derivatives emerges as a possible reason.
Insights
New carborane inhibitors show promise in overcoming cancer drug resistance by targeting ABCG2 transporter proteins. These compounds enhance chemotherapy efficacy, particularly with doxorubicin and cisplatin, suggesting potential for improved cancer treatment strategies.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Pharmacology
Background:
- The ABCG2 transporter protein is implicated in multidrug resistance, limiting cancer therapy effectiveness.
- Previous work identified carborane-functionalized quinazoline derivatives as potent inhibitors of ABCG2.
- These inhibitors have shown potential to reverse breast cancer resistance protein (BCRP)-mediated drug resistance.
Purpose of the Study:
- To evaluate the toxicity and efficacy of promising carboranyl ABCG2 inhibitors in combination with chemotherapeutic agents.
- To assess the potential of these inhibitors to enhance therapeutic efficacy by inhibiting ABCG2.
- To investigate the synergistic effects of co-administering inhibitors with doxorubicin or cisplatin in various cancer cell lines.
Main Methods:
- Evaluation of carboranyl ABCG2 inhibitors' toxicity against ABCG2-expressing cancer cell lines (MCF-7, MCF-7 Doxo, HT29, SW480).
- Co-administration of inhibitors with therapeutic agents (doxorubicin, cisplatin) to assess synergistic effects.
- Measurement of IC50 values to determine the reduction in effective inhibitory concentration of antineoplastic agents.
Main Results:
- Several inhibitors demonstrated synergistic effects when combined with doxorubicin or cisplatin.
- Compounds DMQCa, DMQCc, and DMQCd showed potential to target both ABCB1 and ABCG2 transporters in SW480 cells.
- Co-treatment with DMQCd and doxorubicin halved the effective concentration of doxorubicin in HT29 cells.
- Compound QCe showed synergistic effects with cisplatin in MCF-7 Doxo and HT29 cells, possibly due to inhibition of cisplatin-effluxing ABC transporters.
Conclusions:
- Carboranyl ABCG2 inhibitors can synergize with chemotherapeutic agents like doxorubicin and cisplatin, enhancing their efficacy.
- These compounds show potential for overcoming drug resistance mediated by ABCG2 and possibly ABCB1 transporters.
- The findings support the development of carborane derivatives as adjuncts to cancer therapy to improve treatment outcomes.
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