{"doi":"10.3390/molecules30143014","title":"A Quantitative Model of Chemotherapeutic Drug Sensitivity as a Function of P-Glycoprotein Expression","abstract":"(1) Background: Overexpression of P-glycoprotein (P-gp) is one mediator of multidrug resistance in cancer. While many studies demonstrate the efficacy of modulating P-glycoprotein expression to increase drug response in cancer cells, the nature of the mathematical relationship between drug sensitivity and P-glycoprotein surface density is not yet characterized. (2) Methods: In this study, we employ siRNA to modulate P-gp expression in two model cell lines and evaluate their steady-state response to three common chemotherapeutics in vitro. Additionally, we model the kinetics of calcein-AM, a P-gp substrate, as a function of P-gp expression. (3) Results: For both cell lines, a robust linear relationship governs chemotherapeutic sensitivity as a function of P-gp expression, demonstrating that characterization of P-gp surface density is a strong indicator of drug response in drug-resistant cells. Furthermore, calcein accumulation and initial influx rate exhibit first-order kinetics with respect to P-gp density, further elucidating the nature of substrate interactions with P-gp-overexpressing cells. When transport kinetics are evaluated using a Michaelis–Menten model, Vmax varies with P-gp density according to a first-order relationship. (4) Conclusions: These results establish the mathematical relationships between chemotherapeutic response and substrate influx as a function of P-gp expression and suggest that rational changes in P-gp expression could be used as a predictive measure of drug sensitivity in model cell lines.","journal":"Molecules","year":2025,"id":571298,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9431,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1264652,"name":"N. Kannan","orcid":"0000-0003-2173-5340","position":1,"is_corresponding":false},{"id":339742,"name":"David Putnam","orcid":"0000-0002-0794-4915","position":2,"is_corresponding":false},{"id":1000517,"name":"Cara M. Robertus","orcid":"0000-0002-6230-1509","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:57:15.755535Z","pmid":"40733279","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":[]}