ABSTRACT
The activity of known modulators of the Nrf2 signaling pathway (bardoxolone and brusatol) was studied on cultures of tumor organoids of metastatic colorectal cancer previously obtained from three patients. The effect of modulators was studied both as monotherapy and in combination with standard chemotherapy drugs used to treat colorectal cancer. The Nrf2 inhibitor brusatol and the Nrf2 activator bardoxolone have antitumor activity. Moreover, bardoxolone and brusatol also significantly enhance the effect of the chemotherapy drugs 5-fluorouracil, oxaliplatin, and irinotecan metabolite SN-38. Thus, bardoxolone and brusatol can be considered promising candidates for further preclinical and clinical studies in the treatment of colorectal cancer.
Subject(s)
Colorectal Neoplasms , Fluorouracil , Irinotecan , NF-E2-Related Factor 2 , Organoids , Oxaliplatin , Quassins , Signal Transduction , NF-E2-Related Factor 2/metabolism , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Quassins/pharmacology , Quassins/therapeutic use , Organoids/drug effects , Organoids/metabolism , Organoids/pathology , Signal Transduction/drug effects , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Oxaliplatin/pharmacology , Oxaliplatin/therapeutic use , Irinotecan/pharmacology , Irinotecan/therapeutic use , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Synergism , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Camptothecin/therapeutic useABSTRACT
It was proven that tumor organoids effectively mirror the phenotypic and genetic traits of the original biomaterial. It was reported that outcomes from drug testing in organoid cultures can accurately represent the clinical response observed in patients. In this study, an organoid culture was derived from biopsy material of prostate cancer (PC). Subsequently, clinical practice drugs, docetaxel and enzalutamide, were tested on this organoid culture. Various techniques for evaluating the efficacy of drugs in vitro were compared. The half-maximal inhibitory concentration of docetaxel was found to be markedly lower compared to that of enzalutamide. However, when tested at clinically relevant concentrations and incubation times, enzalutamide was more effective than docetaxel. Therefore, it is crucial to optimize the testing conditions for drugs on in vitro cultures for their subsequent application in clinical practice.