ELIZA

return kwic search for role out of >500 occurrences
507580 occurrences (No.24 in the rank) during 5 years in the PubMed. [cache]

223) MDA-MB-231 cells overexpressing copper transporter hCTR1 were constructed to evaluate its intermediate role in CuET accumulation.

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PMID:33762296 DOI:10.1124/dmd.120.000317

2021 Drug metabolism and disposition: the biological fate of chemicals

* Dual Action of Acidic Microenvironment on the Enrichment of the Active Metabolite of Disulfiram in Tumor Tissues.

- Disulfiram, an antialcoholism drug, could potentially be repurposed as an anticancer drug because of the formation of copper(II) diethyldithiocarbamate (CuET) from dithiocarb (DTC, a reduced metabolite of disulfiram) and Cu²⁺ CuET exhibited preferential distribution to tumor tissues. This study investigated the mechanism of CuET accumulation in tumor tissues by employing MDA-MB-231 human breast cancer cells. The concentration of CuET in cells treated with DTC and Cu²⁺ in acidic culture medium (pH 6.8) was significantly higher than that of the control group (pH 7.4). Subsequently, the effects of pH on the uptake of DTC, Cu²⁺, and CuET were investigated separately. The acidic environment significantly increased the uptake rate of DTC and Cu²⁺ but had no effect on CuET. MDA-MB-231 cells overexpressing copper transporter hCTR1 were constructed to evaluate its intermediate role in CuET accumulation. After treatment with CuCl₂ followed by DTC for 15 minutes, the levels of CuET and Cu²⁺ in hCTR1-overexpressed cells were 2.5 times as much as those of vector group. In the tumors of cancer xenograft models constructed by hCTR1-MDA-MB-231 cells, the concentrations of CuET and Cu were also significantly higher than those of control group. In conclusion, the acidic microenvironment of tumors can promote the enrichment of CuET in tumors through dual action. On the one hand, it can promote transmembrane transport of DTC by converting ionic DTC into molecular state. On the other hand, it enhances Cu²⁺ uptake by activating hCTR1, which ultimately leads to the enrichment of CuET. SIGNIFICANCE STATEMENT: Increasing evidence suggests that the antitumor activity of disulfiram is related to the formation of a copper(II) diethyldithiocarbamate (CuET) of its reducing metabolite dithiocarb with copper(II) ion, which is preferentially distributed in tumor tissues. We showed that the acidic microenvironment, a common feature of many solid tumor tissues, could promote intracellular CuET accumulation through dual action without changing CuET uptake. This result is helpful for the formulation of clinical dosage regimens of disulfiram in cancer treatment.

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(1)215 of	(4)9 null	(7)5 as
(2)199 in	(5)8 and	(8)3 by
(3)23 for	(6)6 that	(9)2 is

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--- WordNet output for role --- =>役目, 役割, 任務, 職務, 役 Overview of noun role The noun role has 4 senses (first 4 from tagged texts) 1. (34) function, office, part, role -- (the actions and activities assigned to or required or expected of a person or group; "the function of a teacher"; "the government must do its part"; "play its role") 2. (10) character, role, theatrical role, part, persona -- (an actor's portrayal of someone in a play; "she played the part of Desdemona") 3. (8) function, purpose, role, use -- (what something is used for; "the function of an auger is to bore holes"; "ballet is beautiful but what use is it?") 4. (6) role -- (normal or customary activity of a person in a particular social setting; "what is your role on the team?") --- WordNet end ---