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The positive inotropic agent DPI-201106 selectively reverses ABCB1-mediated multidrug resistance in cancer cell lines
Sung-Han Hsiao1, Megumi Murakami2, Ni Yeh3
1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Abstract:
The overexpression of ABCB1 in cancer cells is a major factor contributing to the development of multidrug resistance (MDR) and treatment failure in cancer patients. Therefore, re-sensitization of MDR cancer cells to anticancer drugs remains an important aspect in chemotherapy. The progress in developing clinically applicable synthetic inhibitors of ABCB1 has been slow, mostly due to complications associated with intrinsic toxicities and unforeseen drug-drug interactions. Here, we explored the drug-repositioning approach for cancer therapy by targeting ABCB1-mediated MDR in human cancer cells. We found that DPI-201106, a positive inotropic agent, selectively inhibits the drug efflux function of ABCB1, and in doing so, re-sensitizes ABCB1-overexpressing MDR cancer cells to conventional anticancer drugs. Furthermore, the ATPase activity of ABCB1 and docking analysis of DPI-201106 in the drug-binding pocket of ABCB1 were determined to confirm the interaction between DPI-201106 and ABCB1 protein. In summary, we revealed an additional action and a potential clinical application of DPI-201106 to reverse ABCB1-mediated MDR in human cancer cells, which may be beneficial for cancer patients who have developed multidrug resistance and no longer respond to conventional chemotherapy, and should be further investigated.
Insights
DPI-201106, a repurposed drug, effectively reverses multidrug resistance (MDR) in cancer cells by inhibiting ABCB1. This finding offers a new strategy to improve chemotherapy efficacy for patients with treatment-resistant cancers.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- ABCB1 overexpression in cancer cells drives multidrug resistance (MDR) and chemotherapy failure.
- Developing synthetic ABCB1 inhibitors is challenging due to toxicity and drug interactions.
- Targeting ABCB1-mediated MDR is crucial for improving cancer treatment outcomes.
Purpose of the Study:
- To explore drug repositioning for targeting ABCB1-mediated MDR in human cancer cells.
- To investigate the potential of DPI-201106 to re-sensitize MDR cancer cells to conventional chemotherapy.
- To confirm the interaction mechanism between DPI-201106 and the ABCB1 protein.
Main Methods:
- Drug repositioning approach utilizing DPI-201106.
- Assessing the inhibition of ABCB1 drug efflux function.
- Measuring ABCB1 ATPase activity and performing molecular docking analysis.
- Evaluating the re-sensitization of MDR cancer cells to anticancer drugs.
Main Results:
- DPI-201106 selectively inhibits the drug efflux function of ABCB1.
- DPI-201106 re-sensitizes ABCB1-overexpressing MDR cancer cells to conventional anticancer drugs.
- Confirmation of DPI-201106 binding to the ABCB1 protein via ATPase activity and docking studies.
Conclusions:
- DPI-201106 demonstrates a novel application in reversing ABCB1-mediated MDR.
- This drug repositioning strategy holds potential clinical benefits for chemotherapy-resistant cancer patients.
- Further investigation of DPI-201106 is warranted for its clinical application in overcoming MDR.
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