TY - JOUR

T1 - Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer

AU - Lima, Thiago S.

AU - Souza, Luciano O.

AU - Iglesias-Gato, Diego

AU - Elversang, Johanna

AU - Jørgensen, Flemming Steen

AU - Kallunki, Tuula

AU - Røder, Martin A.

AU - Brasso, Klaus

AU - Moreira, José M.A.

N1 - Funding Information: TL, LS, DI-G, FJ, and TK were responsible for acquisition, formal analysis, and interpretation of data. JE, TK, MR, KB, and JM conceived the study and supervised the work. MR, KB, and JM were responsible for funding acquisition. TL, LS, DI-G, JE, FJ, TK, MR, KB, and JM drafted the manuscript or substantively revised it. All authors reviewed the results and approved the final version of the manuscript.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - androgen independence

KW - cellular models

KW - docetaxel resistance

KW - drug repurposing

KW - metastatic castration-resistant prostate cancer

U2 - 10.3389/fphar.2022.869461

DO - 10.3389/fphar.2022.869461

M3 - Journal article

C2 - 35721223

AN - SCOPUS:85133250846

VL - 13

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

SN - 1663-9812

M1 - 869461

ER -