Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer
Docetaxel (DTX) was the first chemotherapeutic agent to demonstrate significant efficacy in the treatment of men with metastatic castration-resistant prostate cancer. However, response to DTX is generally short-lived, and relapse eventually occurs due to emergence of drug-resistance. We previously e...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.869461/full |
| _version_ | 1811336222450122752 |
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| author | Thiago S. Lima Thiago S. Lima Luciano O. Souza Luciano O. Souza Diego Iglesias-Gato Johanna Elversang Flemming Steen Jørgensen Tuula Kallunki Tuula Kallunki Martin A. Røder Martin A. Røder Klaus Brasso José M.A. Moreira |
| author_facet | Thiago S. Lima Thiago S. Lima Luciano O. Souza Luciano O. Souza Diego Iglesias-Gato Johanna Elversang Flemming Steen Jørgensen Tuula Kallunki Tuula Kallunki Martin A. Røder Martin A. Røder Klaus Brasso José M.A. Moreira |
| author_sort | Thiago S. Lima |
| collection | DOAJ |
| description | Docetaxel (DTX) was the first chemotherapeutic agent to demonstrate significant efficacy in the treatment of men with metastatic castration-resistant prostate cancer. However, response to DTX is generally short-lived, and relapse eventually occurs due to emergence of drug-resistance. We previously established two DTX-resistant prostate cancer cell lines, LNCaPR and C4-2BR, derived from the androgen‐dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line, respectively. Using an unbiased drug screen, we identify itraconazole (ITZ), an oral antifungal drug, as a compound that can efficiently re-sensitize drug-resistant LNCaPR and C4-2BR prostate cancer cells to DTX treatment. ITZ can re-sensitize multiple DTX-resistant cell models, not only in prostate cancer derived cells, such as PC-3 and DU145, but also in docetaxel-resistant breast cancer cells. This effect is dependent on expression of ATP-binding cassette (ABC) transporter protein ABCB1, also known as P-glycoprotein (P-gp). Molecular modeling of ITZ bound to ABCB1, indicates that ITZ binds tightly to the inward-facing form of ABCB1 thereby inhibiting the transport of DTX. Our results suggest that ITZ may provide a feasible approach to re-sensitization of DTX resistant cells, which would add to the life-prolonging effects of DTX in men with metastatic castration-resistant prostate cancer. |
| first_indexed | 2024-04-13T17:35:19Z |
| format | Article |
| id | doaj.art-b1a3ecbd14b041b09850e5e16f85f1fd |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T17:35:19Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-b1a3ecbd14b041b09850e5e16f85f1fd2022-12-22T02:37:22ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-06-011310.3389/fphar.2022.869461869461Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate CancerThiago S. Lima0Thiago S. Lima1Luciano O. Souza2Luciano O. Souza3Diego Iglesias-Gato4Johanna Elversang5Flemming Steen Jørgensen6Tuula Kallunki7Tuula Kallunki8Martin A. Røder9Martin A. Røder10Klaus Brasso11José M.A. Moreira12Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkCAPES Foundation, Ministry of Education of Brazil, Brasília, BrazilDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkSino-Danish Center for Education and Research, Aarhus University, Aarhus, DenmarkDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkCancer Invasion and Resistance, Danish Cancer Society Research Center, Copenhagen, DenmarkDepartment of Urology, Copenhagen Prostate Cancer Center, Center for Cancer and Organ Disease—Rigshospitalet, Copenhagen University Hospital, Copenhagen, DenmarkDepartment of Clinical Medicine, University of Copenhagen, Copenhagen, DenmarkDepartment of Urology, Copenhagen Prostate Cancer Center, Center for Cancer and Organ Disease—Rigshospitalet, Copenhagen University Hospital, Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDocetaxel (DTX) was the first chemotherapeutic agent to demonstrate significant efficacy in the treatment of men with metastatic castration-resistant prostate cancer. However, response to DTX is generally short-lived, and relapse eventually occurs due to emergence of drug-resistance. We previously established two DTX-resistant prostate cancer cell lines, LNCaPR and C4-2BR, derived from the androgen‐dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line, respectively. Using an unbiased drug screen, we identify itraconazole (ITZ), an oral antifungal drug, as a compound that can efficiently re-sensitize drug-resistant LNCaPR and C4-2BR prostate cancer cells to DTX treatment. ITZ can re-sensitize multiple DTX-resistant cell models, not only in prostate cancer derived cells, such as PC-3 and DU145, but also in docetaxel-resistant breast cancer cells. This effect is dependent on expression of ATP-binding cassette (ABC) transporter protein ABCB1, also known as P-glycoprotein (P-gp). Molecular modeling of ITZ bound to ABCB1, indicates that ITZ binds tightly to the inward-facing form of ABCB1 thereby inhibiting the transport of DTX. Our results suggest that ITZ may provide a feasible approach to re-sensitization of DTX resistant cells, which would add to the life-prolonging effects of DTX in men with metastatic castration-resistant prostate cancer.https://www.frontiersin.org/articles/10.3389/fphar.2022.869461/fullmetastatic castration-resistant prostate cancerdocetaxel resistancecellular modelsandrogen independencedrug repurposing |
| spellingShingle | Thiago S. Lima Thiago S. Lima Luciano O. Souza Luciano O. Souza Diego Iglesias-Gato Johanna Elversang Flemming Steen Jørgensen Tuula Kallunki Tuula Kallunki Martin A. Røder Martin A. Røder Klaus Brasso José M.A. Moreira Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer Frontiers in Pharmacology metastatic castration-resistant prostate cancer docetaxel resistance cellular models androgen independence drug repurposing |
| title | Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer |
| title_full | Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer |
| title_fullStr | Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer |
| title_full_unstemmed | Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer |
| title_short | Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer |
| title_sort | itraconazole reverts abcb1 mediated docetaxel resistance in prostate cancer |
| topic | metastatic castration-resistant prostate cancer docetaxel resistance cellular models androgen independence drug repurposing |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.869461/full |
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