Comprehensive Evaluation of Multiple Approaches Targeting ABCB1 to Resensitize Docetaxel-Resistant Prostate Cancer Cell Lines

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

Abstract

Docetaxel (DTX) is a mainstay in the treatment of metastatic prostate cancer. Failure of DTX therapy is often associated with multidrug resistance caused by overexpression of efflux membrane transporters of the ABC family such as the glycoprotein ABCB1. This study investigated multiple approaches targeting ABCB1 to resensitize DTX-resistant (DTXR) prostate cancer cell lines. In DU145 DTXR and PC-3 DTXR cells as well as age-matched parental controls, the expression of selected ABC transporters was analyzed by quantitative PCR, Western blot, flow cytometry and immunofluorescence. ABCB1 effluxing activity was studied using the fluorescent ABCB1 substrate rhodamine 123. The influence of ABCB1 inhibitors (elacridar, tariquidar), ABCB1-specific siRNA and inhibition of post-translational glycosylation on DTX tolerance was assessed by cell viability and colony formation assays. In DTXR cells, only ABCB1 was highly upregulated, which was accompanied by a strong effluxing activity and additional post-translational glycosylation of ABCB1. Pharmacological inhibition and siRNA-mediated knockdown of ABCB1 completely resensitized DTXR cells to DTX. Inhibition of glycosylation with tunicamycin affected DTX resistance partially in DU145 DTXR cells, which was accompanied by a slight intracellular accumulation and decreased effluxing activity of ABCB1. In conclusion, DTX resistance can be reversed by various strategies with small molecule inhibitors representing the most promising and feasible approach.

Details

OriginalspracheEnglisch
Seiten (von - bis)1-23
Seitenumfang23
FachzeitschriftInternational journal of molecular sciences
Jahrgang24
Ausgabenummer1
PublikationsstatusVeröffentlicht - 30 Dez. 2022
Peer-Review-StatusJa

Externe IDs

Scopus 85145925617
ORCID /0000-0003-3717-3637/work/141545163
ORCID /0000-0002-5247-908X/work/142241952
PubMed 36614114
PubMedCentral PMC9820728

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Male, Humans, Docetaxel/pharmacology, Taxoids/therapeutic use, Drug Resistance, Neoplasm/genetics, Cell Line, Tumor, Prostatic Neoplasms/drug therapy, RNA, Small Interfering/pharmacology, Antineoplastic Agents/therapeutic use, ATP Binding Cassette Transporter, Subfamily B/genetics