Matches in SemOpenAlex for { <https://semopenalex.org/work/W3178016259> ?p ?o ?g. }
Showing items 1 to 96 of
96
with 100 items per page.
- W3178016259 abstract "Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Though most patients initially respond to platinum-based therapy, the likelihood of disease reoccurrence is nearly 100%. Thus, new tumor-selective therapies for EOC are urgently needed. One such treatment option involves targeting tumors via folate receptor α (FRα), which is overexpressed in up to 90% of EOCs and shows increasing expression with higher stage and grade of disease. Our laboratory discovered novel 5-substituted pyrrolo[3,2-d]pyrimidine analogs (AGF347, AGF359, AGF362 and AGF363) that inhibit mitochondrial one-carbon (C1) metabolism at serine hydroxymethyltransferase (SHMT) 2, with secondary inhibition at cytosolic enzyme targets including those in de novo purine biosynthesis. Potent inhibition was seen with several FRα-expressing EOC tumor cells. Inhibitory potencies were in order, AGF347 > AGF359 > AGF362 > AGF363. Drug effects were substantially reduced with excess folic acid (FA), confirming FRα-mediated drug uptake. Toward cisplatin resistant SKOV3, TOV112D and A2780 EOC cells, inhibition in the nanomolar range was detected with all compounds. Targeted metabolomics, using L-[2,3,3-2H]serine as a tracer in wild-type or SHMT2 knockdown SKOV3 cells, confirmed all compounds inhibited cytosolic and mitochondrial C1-metabolism (at SHMT2). Apoptosis was detected for all compounds by Annexin V/PI, with partial rescue of apoptosis observed upon addition of glutathione (GSH). Glutathione pools (GSH and total GSH+GSSG) were significantly perturbed by drug treatment with all inhibitors in SKOV3 cells, comparable to GSH levels observed in SHMT2 KD cells. In vivo efficacy studies with SKOV3 xenografts treated with either AGF347 or cisplatin in SCID mice showed cisplatin resistance, while AGF347 demonstrated efficacy and delay in disease progression with a median tumor growth delay of 10 days, with the longest delay being 15 days. Our studies describe a series of novel inhibitors targeting mitochondrial and cytosolic C1-metabolism, selectively delivered via FRα, which show direct cytotoxic effects against cisplatin resistant EOC in vitro and in vivo, and display additional mechanisms of cytotoxicity mediated through glycine depletion.Citation Format: Adrianne C. Wallace-Povirk, Carrie O'Connor, Xun Bao, Jade Katinas, Jennifer Wong-Roushar, Aamod Dekhne, Zhanjun Hou, Md. Junayed Nayeen, Khushbu Shah, Jose Cardiel Nunez, Jing Li, Seongho Kim, Lisa Polin, Charles E. Dann, Aleem Gangjee, Larry H. Matherly. Targeting mitochondrial and cytosolic one-carbon metabolism in epithelial ovarian cancer via folate receptor alpha [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2348." @default.
- W3178016259 created "2021-07-19" @default.
- W3178016259 creator A5012677271 @default.
- W3178016259 creator A5016984099 @default.
- W3178016259 creator A5017584174 @default.
- W3178016259 creator A5024844590 @default.
- W3178016259 creator A5037364310 @default.
- W3178016259 creator A5049202147 @default.
- W3178016259 creator A5049353848 @default.
- W3178016259 creator A5052708209 @default.
- W3178016259 creator A5061919970 @default.
- W3178016259 creator A5065717250 @default.
- W3178016259 creator A5066746739 @default.
- W3178016259 creator A5074407593 @default.
- W3178016259 creator A5076637491 @default.
- W3178016259 creator A5077860460 @default.
- W3178016259 creator A5081100839 @default.
- W3178016259 creator A5084102458 @default.
- W3178016259 date "2021-07-01" @default.
- W3178016259 modified "2023-10-16" @default.
- W3178016259 title "Abstract 2348: Targeting mitochondrial and cytosolic one-carbon metabolism in epithelial ovarian cancer via folate receptor alpha" @default.
- W3178016259 doi "https://doi.org/10.1158/1538-7445.am2021-2348" @default.
- W3178016259 hasPublicationYear "2021" @default.
- W3178016259 type Work @default.
- W3178016259 sameAs 3178016259 @default.
- W3178016259 citedByCount "0" @default.
- W3178016259 crossrefType "proceedings-article" @default.
- W3178016259 hasAuthorship W3178016259A5012677271 @default.
- W3178016259 hasAuthorship W3178016259A5016984099 @default.
- W3178016259 hasAuthorship W3178016259A5017584174 @default.
- W3178016259 hasAuthorship W3178016259A5024844590 @default.
- W3178016259 hasAuthorship W3178016259A5037364310 @default.
- W3178016259 hasAuthorship W3178016259A5049202147 @default.
- W3178016259 hasAuthorship W3178016259A5049353848 @default.
- W3178016259 hasAuthorship W3178016259A5052708209 @default.
- W3178016259 hasAuthorship W3178016259A5061919970 @default.
- W3178016259 hasAuthorship W3178016259A5065717250 @default.
- W3178016259 hasAuthorship W3178016259A5066746739 @default.
- W3178016259 hasAuthorship W3178016259A5074407593 @default.
- W3178016259 hasAuthorship W3178016259A5076637491 @default.
- W3178016259 hasAuthorship W3178016259A5077860460 @default.
- W3178016259 hasAuthorship W3178016259A5081100839 @default.
- W3178016259 hasAuthorship W3178016259A5084102458 @default.
- W3178016259 hasConcept C121608353 @default.
- W3178016259 hasConcept C126322002 @default.
- W3178016259 hasConcept C181199279 @default.
- W3178016259 hasConcept C185592680 @default.
- W3178016259 hasConcept C190283241 @default.
- W3178016259 hasConcept C2776414213 @default.
- W3178016259 hasConcept C2776694085 @default.
- W3178016259 hasConcept C2778239845 @default.
- W3178016259 hasConcept C2779344277 @default.
- W3178016259 hasConcept C2779932687 @default.
- W3178016259 hasConcept C2780306303 @default.
- W3178016259 hasConcept C502942594 @default.
- W3178016259 hasConcept C538909803 @default.
- W3178016259 hasConcept C55493867 @default.
- W3178016259 hasConcept C71924100 @default.
- W3178016259 hasConcept C86803240 @default.
- W3178016259 hasConcept C96232424 @default.
- W3178016259 hasConcept C98274493 @default.
- W3178016259 hasConceptScore W3178016259C121608353 @default.
- W3178016259 hasConceptScore W3178016259C126322002 @default.
- W3178016259 hasConceptScore W3178016259C181199279 @default.
- W3178016259 hasConceptScore W3178016259C185592680 @default.
- W3178016259 hasConceptScore W3178016259C190283241 @default.
- W3178016259 hasConceptScore W3178016259C2776414213 @default.
- W3178016259 hasConceptScore W3178016259C2776694085 @default.
- W3178016259 hasConceptScore W3178016259C2778239845 @default.
- W3178016259 hasConceptScore W3178016259C2779344277 @default.
- W3178016259 hasConceptScore W3178016259C2779932687 @default.
- W3178016259 hasConceptScore W3178016259C2780306303 @default.
- W3178016259 hasConceptScore W3178016259C502942594 @default.
- W3178016259 hasConceptScore W3178016259C538909803 @default.
- W3178016259 hasConceptScore W3178016259C55493867 @default.
- W3178016259 hasConceptScore W3178016259C71924100 @default.
- W3178016259 hasConceptScore W3178016259C86803240 @default.
- W3178016259 hasConceptScore W3178016259C96232424 @default.
- W3178016259 hasConceptScore W3178016259C98274493 @default.
- W3178016259 hasLocation W31780162591 @default.
- W3178016259 hasOpenAccess W3178016259 @default.
- W3178016259 hasPrimaryLocation W31780162591 @default.
- W3178016259 hasRelatedWork W1535356922 @default.
- W3178016259 hasRelatedWork W1586384817 @default.
- W3178016259 hasRelatedWork W2022327359 @default.
- W3178016259 hasRelatedWork W2059858721 @default.
- W3178016259 hasRelatedWork W2078685491 @default.
- W3178016259 hasRelatedWork W2171780956 @default.
- W3178016259 hasRelatedWork W2227411328 @default.
- W3178016259 hasRelatedWork W2775343545 @default.
- W3178016259 hasRelatedWork W2915648405 @default.
- W3178016259 hasRelatedWork W2304798752 @default.
- W3178016259 isParatext "false" @default.
- W3178016259 isRetracted "false" @default.
- W3178016259 magId "3178016259" @default.
- W3178016259 workType "article" @default.