{"doi":"10.1016/j.jacbts.2020.05.012","title":"In Situ Immune Profiling Identifies Immune Players Involved in Allograft Rejection","abstract":"Almost\nall known conventional cytotoxic anticancer drugs are less effective in\nkilling tumor cells grown as multicellular spheroids than in killing\ntumor cells grown as monolayer cell cultures. This“\nmulticellular resistance” reflects the relative intrinsic\ndrug-resistant phenotype of most solid tumors growing in\nvivo and is due to factors such as limited drug penetration or\nreduced fractions of proliferating cells. Proteasome inhibitors such as\nPS-341, a dipeptide boronic acid analogue, represent an interesting new\nclass of potential anticancer drugs, which are entering early-phase\nclinical trials. PS-341 has been found to have good broad-spectrum\ncytotoxic activity in the 60-monolayer cell line National Cancer\nInstitute screen. However, because its relative potency has not been\ntested in spheroid systems, we analyzed the activity of PS-341 in a\nspheroid/solid tumor context using four different human ovarian\ncarcinoma cell lines and three prostate carcinoma cell lines,\nrespectively. We found, with one exception, that PS-341 showed equal or\ngreater activity in spheroids than in the respective monolayer cell\ncultures, even in a prostate cancer spheroid model with a very low\ngrowth fraction. PS-341 induced apoptotic cell death in carcinoma cells\nin both culture systems. We also noted a decrease in XIAP\nprotein, a member of the inhibitor of apoptosis (IAP) family of\napoptosis inhibitors, and phosphorylation of Bcl-XL in\nPS-341-treated ovarian carcinoma cells. Furthermore, DNA fragmentation,\na hallmark of apoptosis (in this case, induced by PS-341), was\ncompletely inhibited by the caspase inhibitor\nN-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD). Taken\ntogether, the results indicate that unlike most other known anticancer\ncytotoxic drugs, PS-341 appears to be as effective in killing tumor\ncells grown in the form of multicell spheroids as in killing tumor\ncells grown in monolayer cell culture. Hence, this compound has the\npotential to circumvent multicellular drug resistance and, as such, may\nshow promising activity against solid tumors with low growth\nfractions invivo, which are frequently\nintrinsically resistant to conventional cytotoxic anticancer drugs.","journal":"JACC Basic to Translational Science","year":2020,"id":116811,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":545683,"name":"Francesco Donatelli","orcid":"0000-0003-2839-0373","position":1,"is_corresponding":false},{"id":545684,"name":"Ciro Maiello","orcid":"0000-0003-1604-4756","position":2,"is_corresponding":false},{"id":242691,"name":"Claudio Napoli","orcid":"0000-0002-5455-555X","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-18T23:13:47.803267Z","pmid":"32754672","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":[]}