Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer

Abstract

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.

Overcoming ABCB1 mediated multidrug resistance in castration resistant prostate cancer

“…In similar studies, elevation of ABCB1 was documented in GEMM after tumors developed resistance to PARP inhibitor olaparib 52 . Expression of ABCB1 was significantly increased in the experimentally produced taxanes-resistant CRPC cell lines by several groups (including current study), thereby recapitulating the clinical response of mCRPC patients 13 , 43 , 53 – 55 . Mechanisms of ABCB1 overexpression include epigenetic changes at ABCB1 regulatory elements 56 , amplification of the ABCB1 gene 55 , and increased activation of transcription factors that regulate ABCB1 expression 57 .…”

“…There are several ways to overcome ABCB1-dependent MDR. First, extensive research is ongoing to design new ABCB1 inhibitors 58 and to repurpose FDA approved drugs that have ABCB1 inhibitor activity 43 , 58 . Given that MDR is common in chemotherapy resistance, efforts have been directed towards the development of new P-glycoprotein inhibitors, such as elacridar, zosuquidar, laniquidar (R101933) and tariquidar (XR9576) 58 .…”

“…Finally, screens to identify chemotherapeutic drugs not substrates to ABCB1 and, therefore, are not excreted by ABCB1, offer promise to identify mediators and tools to overcome ABCB1-dependent taxanes resistance in cell models, that can be further developed for clinical applications. To this end, recent studies have identified nucleotide analogue gemcitabine 62 and antifungal drug itraconazole 43 as active cytotoxic agents in taxanes-resistant PC cells.…”

“…Expression of ABCB1 is elevated in various cancers, including acute myeloid leukemia 38 , ovarian carcinoma 39 , non-small cell lung cancer 40 , breast 41 and PCa 42 . Analysis of ABCB1 levels in chemo-naïve PCa patients have not demonstrated high levels of expression, suggesting that ABCB1 upregulation is a result of acquired resistance 43 .…”

Pharmacological Efficacy of Repurposing Drugs in the Treatment of Prostate Cancer

“…Additionally, itraconazole seems to be beneficial both in monotherapy and in combination with chemotherapy drugs, and in this last case, it improves the patient’s survival rate [ 2 ]. Furthermore it also reverses P-glycoprotein-mediated resistance to chemotherapy, particularly in the case of docetaxel, where itraconazole resensitizes cells that are resistant to it [ 2 , 48 ].…”