Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells

Kenlan, Dasha; Rychahou, Piotr G.; Sviripa, Vitaliy M.; Weiss, Heidi L.; Liu, Chunming; Watt, David S.; Evers, B. Mark

doi:10.1158/1535-7163.mct-15-0634

Cited by 7 publications

(17 citation statements)

References 28 publications

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“…ACC and S6 were selected for analysis because they are downstream effectors of AMPKα that are phosphorylated and dephosphorylated, respectively, with AMPKα activation. As expected based on prior work, FND-4b treatment increased levels of pAMPKα in all five cell lines ( Fig 2 ) [27]. Consistent with this result, increases in pACC and decreases in pS6 were also noted.…”

Section: Resultssupporting

confidence: 91%

Induction of AMPK activation by N,N’-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

et al. 2019

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PurposeTriple negative breast cancer (TNBC) is the most lethal and aggressive subtype of breast cancer. AMP-activated protein kinase (AMPK) is a major energy regulator that suppresses tumor growth, and 1-(3-chloro-4-((trifluoromethyl)thio)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea (FND-4b) is a novel AMPK activator that inhibits growth and induces apoptosis in colon cancer. The purpose of this project was to test the effects of FND-4b on AMPK activation, proliferation, and apoptosis in breast cancer with a particular emphasis on TNBC.Materials and methods(i) Estrogen-receptor positive breast cancer (ER+BC; MCF-7, and T-47D), TNBC (MDA-MB-231 and HCC-1806), and breast cancer stem cells were treated with FND-4b for 24h. Immunoblot analysis assessed AMPK, acetyl-CoA carboxylase (ACC), ribosomal protein S6, cyclin D1, and cleaved PARP. (ii) Sulforhodamine B growth assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h. Proliferation was also assessed by counting cells after 72h of FND-4b treatment. (iii) Cell death ELISA assays were performed after treating ER+BC and TNBC cells with FND-4b for 72h.Results(i) FND-4b increased AMPK activation with concomitant decreases in ACC activity, phosphorylated S6, and cyclin D1 in all subtypes. (ii) FND-4b decreased proliferation in all cells, while dose-dependent growth decreases were found in ER+BC and TNBC. (iii) Increases in apoptosis were observed in ER+BC and the MDA-MB-231 cell line with FND-4b treatment.ConclusionsOur findings indicate that FND-4b decreases proliferation for a variety of breast cancers by activating AMPK and has notable effects on TNBC. The growth reductions were mediated through decreases in fatty acid synthesis (ACC), mTOR signaling (S6), and cell cycle flux (cyclin D1). ER+BC cells were more susceptible to FND-4b-induced apoptosis, but MDA-MB-231 cells still underwent apoptosis with higher dose treatment. Further development of FND compounds could result in a novel therapeutic for TNBC.

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Section: Resultssupporting

confidence: 91%

Induction of AMPK activation by N,N’-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

et al. 2019

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“…There is a formal possibility that phosphorylation of eIF2α was consequence of stress induced by the compound rather than activation of parasite eIF2α kinase, as described for mammalian cells 21 . For example, a modified urea derivative was shown to interact with mammalian CXCR2 receptor preventing signaling 43 , and fluorinated 1,3-diarylureas were found to activate AMP-activated protein kinase, inhibiting cell-cycle progression and proliferation in colorectal and stem cells cancers 44 . This, however, is unlikely to occur in T. cruzi as eight closely related analogs (3b, 3n, 3d, 3j, 3k, 3l, 3t and NCPdCPU) which failed to activate mammalian eIF2α kinases also have no activity against parasites 23 , 26 .…”

Section: Discussionmentioning

confidence: 99%

Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation

Machado

Franco

Neto

et al. 2018

Sci Rep

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Some 1,3-diarylureas and 1-((1,4-trans)−4-aryloxycyclohexyl)−3-arylureas (cHAUs) activate heme-regulated kinase causing protein synthesis inhibition via phosphorylation of the eukaryotic translation initiation factor 2 (eIF2) in mammalian cancer cells. To evaluate if these agents have potential to inhibit trypanosome multiplication by also affecting the phosphorylation of eIF2 alpha subunit (eIF2α), we tested 25 analogs of 1,3-diarylureas and cHAUs against Trypanosoma cruzi, the agent of Chagas disease. One of them (I-17) presented selectivity close to 10-fold against the insect replicative forms and also inhibited the multiplication of T. cruzi inside mammalian cells with an EC50 of 1–3 µM and a selectivity of 17-fold. I-17 also prevented replication of African trypanosomes (Trypanosoma brucei bloodstream and procyclic forms) at similar doses. It caused changes in the T. cruzi morphology, arrested parasite cell cycle in G1 phase, and promoted phosphorylation of eIF2α with a robust decrease in ribosome association with mRNA. The activity against T. brucei also implicates eIF2α phosphorylation, as replacement of WT-eIF2α with a non-phosphorylatable eIF2α, or knocking down eIF2 protein kinase-3 by RNAi increased resistance to I-17. Therefore, we demonstrate that eIF2α phosphorylation can be engaged to develop trypanosome-static agents in general, and particularly by interfering with activity of eIF2 kinases.

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“…Many canonical AMPK activities lend themselves to AMPK acting as a tumor suppressor, and therefore loss of expression would promote tumorigenesis (Shackelford and Shaw, 2009 ). Recent work has shown that treatment of colorectal cancer cells and breast cancer cells and tissues with a novel AMPK activator (FNDs) induces apoptosis and cancer cell death (Kenlan et al, 2017 ; Johnson et al, 2019 ). But there is also evidence that AMPK is critical for the maintenance of established tumors and could therefore be targeted for anti-cancer therapies in certain contexts.…”

Section: Ampk Implications In Cancermentioning

confidence: 99%

Interplay Between Calcium and AMPK Signaling in Human Cytomegalovirus Infection

Dunn

Munger

2020

Front. Cell. Infect. Microbiol.

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Calcium signaling and the AMP-activated protein kinase (AMPK) signaling networks broadly regulate numerous aspects of cell biology. Human Cytomegalovirus (HCMV) infection has been found to actively manipulate the calcium-AMPK signaling axis to support infection. Many HCMV genes have been linked to modulating calcium signaling, and HCMV infection has been found to be reliant on calcium signaling and AMPK activation. Here, we focus on the cell biology of calcium and AMPK signaling and what is currently known about how HCMV modulates these pathways to support HCMV infection and potentially contribute to oncomodulation.

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Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells

Cited by 7 publications

References 28 publications

Induction of AMPK activation by N,N’-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

Induction of AMPK activation by N,N’-diarylurea FND-4b decreases growth and increases apoptosis in triple negative and estrogen-receptor positive breast cancers

Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation

Interplay Between Calcium and AMPK Signaling in Human Cytomegalovirus Infection

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