{"doi":"10.3390/ijms22136676","title":"Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells","abstract":"Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells. KPT-8602 synergized with PARPi (CI < 1) at pharmacologically relevant concentrations. KPT-8602-PARPi showed superior induction of apoptosis compared to single agent treatment and caused up-regulation of pro-apoptotic genes BAX, TP53 and CASPASE 9. Mechanistically, KPT-8602-PARPi suppressed AR, ARv7, PSA and AR targets FOXA1 and UBE2C. Western blot analysis revealed significant down-regulation of AR, ARv7, UBE2C, SAM68, FOXA1 and upregulation of cleaved PARP and cleaved CASPASE 3. KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including BRCA1, BRCA2, CHEK1, EXO1, BLM, RAD51, LIG1, XRCC3 and RMI2. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC.","journal":"International Journal of Molecular Sciences","year":2021,"id":183992,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9518,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":696563,"name":"Yiwei Li","orcid":"0000-0003-2389-3203","position":1,"is_corresponding":false},{"id":469418,"name":"Husain Yar Khan","orcid":"0000-0002-9161-1514","position":2,"is_corresponding":false},{"id":708555,"name":"Irfana Muqbil","orcid":"0000-0001-6889-7035","position":3,"is_corresponding":false},{"id":470519,"name":"Amro Aboukameel","orcid":null,"position":4,"is_corresponding":false},{"id":469420,"name":"Rachel Sexton","orcid":"0000-0002-0008-9629","position":5,"is_corresponding":false},{"id":738449,"name":"Shriya Reddy","orcid":"0000-0002-7047-4354","position":6,"is_corresponding":false},{"id":308468,"name":"Yosef Landesman","orcid":"0000-0001-5542-5098","position":7,"is_corresponding":false},{"id":309951,"name":"Trinayan Kashyap","orcid":null,"position":8,"is_corresponding":false},{"id":469428,"name":"Asfar S. Azmi","orcid":"0000-0003-1178-9505","position":9,"is_corresponding":false},{"id":54382,"name":"Elisabeth I. Heath","orcid":"0000-0003-1381-2713","position":10,"is_corresponding":false},{"id":402158,"name":"Md. Hafiz Uddin","orcid":"0000-0002-0188-6857","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T23:48:26.340498Z","pmid":"34206543","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}