Scholarly Journals--Published

  • Dibenzyl trisulfide binds to and competitively inhibits the cytochrome P450 1A1 active site without impacting the expression of the aryl hydrocarbon receptor. Wauchope S, Roy MA, Irvine W, Morrison I, Brantley E, Gossell-Williams M, Timme-Laragy AR, Delgoda R. Toxicol Appl Pharmacol. 2021 May 15;419:115502. doi: 10.1016/j.taap.2021.115502. Epub 2021 Mar 24. PMID: 33774063 (05/2021)
  •     Cancer stem cells: Culprits in endocrine resistance and racial disparities in breast cancer outcomes. Mavingire N, Campbell P, Wooten J, Aja J, Davis MB, Loaiza-Perez A, Brantley E. Cancer Lett. 2021 Mar 1;500:64-74. doi: 10.1016/j.canlet.2020.12.014. Epub 2020 Dec 9. PMID: 33309858 (03/2021)
  • Rowland LK, Campbell PS, Mavingire N, Wooten JV, McLean L, Zylstra D, Thorne G, Daly D, Boyle K, Whang S, Unternaehrer J, Brantley EJ. Putative tumor suppressor cytoglobin promotes aryl hydrocarbon receptor ligand-mediated triple negative breast cancer cell death. J Cell Biochem. 2019 Apr;120(4):6004-6014. doi: 10.1002/jcb.27887. Epub 2018 Nov 18. Putative tumor suppressor cytoglobin promotes aryl hydrocarbon receptor ligand-mediated triple negative breast cancer cell death. (11/2019)
  • Brantley E, Callero MA, Berardi D, Campbell p, Yee M, Amis L, Todaro L, Simian M, Loaiza-Perez A and Soto U. Aminoflavone inhibits alpha 6 integrin expression and breast cancer sphere-initiating capacity. 2016. Cancer Lett Jun 28;376 (1):53-61. (10/2018)
  • Campbell PS, Mavingire N, Khan S, Rowland LK, Wooten JV, Opoku-Agyeman A, Guevara A, Soto U, Cavalli F, Loaiza-Perez AI, Nagaraj G, Denham LJ, Adeoye O, Jenkins BD, Davis MB, Schiff R and Brantley EJ. AhR ligand aminoflavone suppresses alpha 6-integrin-Src-Akt signaling to attenuate tamoxifen resistance in breast cancer cells. J Cell Physiol. 2018 Aug 4. (08/2018)
  • Badal S, Huang G, Vendantam P, Francis S, Asuncion Valenzuela M, Quitugua A, Amis L, Davis W, Tzeng T, Jacos H, Gangemi D, Raner G, Rowland L, Wooten J, Campbell P, Brantley E and Delgoda R. Glaucarubulone glycoside attenuates procarcinogen-mediated CYP1 gene induction and supresses cancer cell growth. J. Appl. Toxicol. 2017 Jul: 37(7): 873-883. (07/2017)
  • Xu D, Karain B, Brantley E, & Shi W X. (2011). Effects of L-DOPA on Nigral Dopamine Neurons and Local Field Potential: Comparison with Apomorphine and Muscimol. Journal of Pharmacology and Experimental Therapeutics, 337(2), 533-539. L-DOPA is more effective than direct dopamine (DA) agonists in relieving the motor deficits in Parkinson's disease. Using in vivo recording, we compared the effect of L-DOPA and the direct DA agonist apomorphine on DA neurons in rat substantia nigra (SN). L-DOPA (50-100 mg/kg i.v.) decreased the firing rate as well as the variability and slow oscillation (SO) of firing. All effects were blocked by raclopride and mimicked by quinpirole, suggesting that they are mediated through D2-like receptors. Autoreceptor-selective doses of apomorphine (5-20 mu g/kg i.v.) also inhibited all three parameters. The magnitude of the inhibition, however, was significantly greater than that induced by L-DOPA. Neither L-DOPA nor apomorphine had a consistent effect on SN local field potentials (LFPs). The GABA agonist muscimol, known to preferentially inhibit SN non-DA neurons, consistently inhibited the SO in both DA cell firing and LFPs. These results suggest that SN LFPs mainly reflect the synaptic potentials in non-DA neurons, and L-DOPA and apomorphine, unlike muscimol, affect DA neurons primarily through DA autoreceptors. DA autoreceptor activation is known to hyperpolarize DA cells by increasing the membrane conductance to K(+). This increase in membrane conductance would shunt synaptic input to DA neurons, thereby decreasing the variability and SO in DA cell firing. The low potency of L-DOPA to inhibit DA cell firing and reduce their responses to synaptic input may partially account for its superior therapeutic efficacy in Parkinson's disease compared with apomorphine and other direct DA agonists. (05/2011) (link)
  • McLean, L., Soto, U., Agama, K., Francis, J., Jimenez, R., Pommier, Y., Sowers, L. and Brantley, E. “Aminoflavone induced oxidative DNA damage and reactive oxygen species-mediated apoptosis in breast cancer cells”.  Int J. Cancer. 2008 April 122: 1665-1674. Epub 2007 Dec 4. Code:1 (04/2008)
  • Eileen Brantley, Smitha Anthony, Glenda Kohlhagen, LingHua Meng, Keli Agama, Sherman Stinson, Edward Sausville, Yves Pommier. "Anti-tumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces single-strand breaks and DNA-protein cross-links in sensitive MCF-7 breast cancer cells." Cancer Chemotherapy and Pharmacology 58.1 (2006): 62-72 Code:1. The fluorinated benzothiazole analogue 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) exhibits selective and potent anticancer activity, and its lysylamide prodrug (Phortress, NSC 710305) recently entered Phase I clinical trials in the United Kingdom. Only cancer cells sensitive to the anti-proliferative effects of 5F 203 deplete this drug candidate from nutrient media. 5F 203 induces cell cycle arrest, cytochrome P450 1A1 (CYP 1A1) mRNA and protein expression, and is metabolized into reactive electrophilic species that can covalently bind to DNA and form adducts in sensitive (i.e., MCF-7) but not in resistant (i.e., MDA-MB-435) breast cancer cells. In this present study, we investigated additional anticancer effects of 5F 203 in MCF-7 cells. In addition, we sought to determine if cells deficient in the xeroderma pigmentosum D gene, a gene critical in DNA repair, would show greater sensitivity to the cytotoxic effects of 5F 203 than those complemented with XPD. Alkaline Elution revealed that 5F 203 induced single-strand breaks and DNA-protein cross-links in sensitive MCF-7 cells. In contrast, no double-strand breaks or protein-associated strand breaks were detected in sensitive MCF-7 cells typically associated with topoisomerase I (top1) or topoisomerase II (top2) inhibition. In addition, 5F 203 was unable to trap top1- or top2-DNA cleavage complexes in MCF-7 cells. 5F 203 induced cell cycle arrest in MCF-7 cells following DNA damage after brief exposures. Cells deficient in the nucleotide excision repair Xeroderma Pigmentosum group D (XPD) gene displayed sensitivity to 5F 203 while cells complemented with XPD displayed resistance to 5F 203. These data suggest that the anti-cancer activity of 5F 203 depends upon targets other than top1 or top2 and on the ability of this benzothiazole to form single-strand breaks and DNA-protein cross-links in cancer cells. (07/2006)
  • Brantley, E., Patel, V., Hose, C., Ciolino, H.P., Yeh, G.C., Trapani, V., Stinson, S.F., Sausville, E.A. and Loaiza-Pérez, A.I. "The antitumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces NF-kappaB activity in drug-sensitive MCF-7 cells." Anticancer Drugs 16.2 (2005): 137-143 Code: 1. 2-(4-Amino-3-methylphenyl)-5-fluoro-benzothiazole (5F 203) potently inhibits MCF-7 breast cancer cell growth in part by activating the aryl hydrocarbon receptor (AhR) signaling pathway. Ligands for the AhR (i.e. dioxin) have also been shown to modulate the NF-kappaB signaling cascade, affecting physiological processes such as cellular immunity, inflammation, proliferation and survival. The objective of this study was to investigate the effect of 5F 203 treatment on the NF-kappaB signaling pathway in breast cancer cells. Exposure of MCF-7 cells to 5F 203 increased protein-DNA complex formation on the NF-kappaB-responsive element as determined by electrophoretic mobility shift assay, but this effect was eliminated in MDA-MB-435 cells, which are resistant to the antiproliferative effects of 5F 203. An increase in NF-kappaB-dependent transcriptional activity was confirmed by a significant increase in NF-kappaB-dependent reporter activity in sensitive MCF-7 cells, which was absent in resistant MDA-MB-435 cells and AhR-deficient subclones of MCF-7 cells. Inhibition of NF-kappaB activation enhanced the increase in xenobiotic response element-dependent reporter activity in MCF-7 cells when treated with 5F 203. The drug candidate 5F 203 also induced mRNA levels of IL-6, an NF-kappaB-responsive gene, in MCF-7 cells, but not in MDA-MB-435 cells, as determined by quantitative RT-PCR. These findings suggest that 5F 203 activation of the NF-kappaB signaling cascade may contribute to 5F 203-mediated anticancer activity in human breast cancer MCF-7 cells (02/2005)
  • Brantley, E., Trapani, V., Alley M.C., Hose, C.D., Bradshaw, T.D., Stevens, M.F.G. and Stinson, S.F. . "Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles are metabolized and bind to sub-cellular macromolecules in sensitive human cancer cells." Drug Metabolism and Disposition 32.12 (2004): 1392-1401 Code:1. Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles possess potent antiproliferative activity against certain cancer cells, similar to the unfluorinated 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495). In "sensitive" cancer cells, DF 203 is metabolized by, can induce expression of, and binds covalently to CYP1A1. Metabolism appears to be essential for its antiproliferative activity through DNA adduct formation. However, a biphasic dose-response relationship compromises its straightforward development as a chemotherapeutic agent. We investigated whether fluorinated benzothiazoles inhibit cancer cell growth without the biphasic dose-response, and whether the fluorinated benzothiazoles are also metabolized into reactive species, with binding to macromolecules in sensitive cancer cells. One fluorinated benzothiazole, 2-(4-amino-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) did exhibit potent, antiproliferative activity without a biphasic dose-response. The fluorinated benzothiazoles were also metabolized only in cells, which subsequently showed evidence of cell death. We used microsomes from genetically engineered human B-lymphoblastoid cells expressing cytochromes P450 (CYP1A1, CYP1A2, or CYP1B1) to clarify the basis for fluorinated benzothiazole metabolism. 5F 203 induced CYP1A1 and CYP1B1 mRNA expression in sensitive breast and renal cancer cells, whereas 5F 203 induced CYP1A1 mRNA but not CYP1B1 mRNA expression in sensitive ovarian cancer cells. 5F 203 did not induce CYP1A1 or CYP1B1 mRNA expression in any "resistant" cancer cells. The fluorinated benzothiazoles induced CYP1A1 protein expression exclusively in sensitive cells. [14C]5F 203 bound substantially to subcellular fractions in sensitive cells but only minimally in resistant cells. These data are concordant with the antiproliferative activity of fluorinated benzothiazoles deriving from their ability to become metabolized and bind to macromolecules within sensitive cells. (12/2004)

Scholarly Journals--Accepted

  • Rowland LK, Campbell PS, Mavingire N, Khan S, Wooten JV, McLean LS, Zylstra D, Thorne G, Daly D, Boyle K, Whang S, Unternaehrer J and Brantley EJ. Putative tumor suppressor cytoglobin promotes aryl hydrocarbon receptor ligand-mediated triple negative breast cancer cell death. In Press (08/2018)


  • McLean L S, & Brantley E. (2013). Apoptotic mechanism of novel anticancer agents is mediated by MAPKs in breast cancer cells. FASEB Journal, 27, 1. (04/2013)