1.Anti-tumor activity and mechanism of action for a cyanoaziridine-derivative, AMP423.
Dorr RT1, Wisner L, Samulitis BK, Landowski TH, Remers WA. Cancer Chemother Pharmacol. 2012 Apr;69(4):1039-49. doi: 10.1007/s00280-011-1784-8. Epub 2011 Dec 21.
PURPOSE: Preclinical studies evaluated the anti-tumor activity and mechanism of action of AMP423, a naphthyl derivative of 2-cyanoaziridine-1-carboxamide with structural similarity to the pro-oxidant anti-tumor agent imexon.
2.Interaction of dacarbazine and imexon, in vitro and in vivo, in human A375 melanoma cells.
Samulitis BK1, Dorr RT, Chow HH. Anticancer Res. 2011 Sep;31(9):2781-5.
AIM: We evaluated mechanisms of interaction between the alkyating agent dacarbazine (DTIC) and the pro-oxidant, imexon, in the human A375 melanoma cell line.
3.Tumor Xenograft Response to Redox-Active Therapies Assessed by Magnetic Resonance Imaging Using a Thiol-Bearing DOTA Complex of Gadolinium.
Guntle GP1, Jagadish B, Mash EA, Powis G, Dorr RT, Raghunand N. Transl Oncol. 2012 Jun;5(3):190-9. Epub 2012 Jun 1.
Gd-LC6-SH is a thiol-bearing DOTA complex of gadolinium designed to bind plasma albumin at the conserved Cys(34) site. The binding of Gd-LC6-SH shows sensitivity to the presence of competing thiols. We hypothesized that Gd-LC6-SH could provide magnetic resonance imaging (MRI) enhancement that is sensitive to tumor redox state and that the prolonged retention of albumin-bound Gd-LC6-SH in vivo can be exploited to identify a saturating dose above which the shortening of MRI longitudinal relaxation time (T(1)) of tissue is insensitive to the injected gadolinium dose. In the Mia-PaCa-2 pancreatic tumor xenograft model in SCID mice, both the small-molecule Gd-DTPA-BMA and the macromolecule Galbumin MRI contrast agents produced dose-dependent decreases in tumor T(1). By contrast, the decreases in tumor T(1) provided by Gd-LC6-SH at 0.05 and 0.1 mmol/kg were not significantly different at longer times after injection. SCID mice bearing Mia-PaCa-2 or NCI-N87 tumor xenografts were treated with either the glutathione synthesis inhibitor buthionine sulfoximine or the thiol-oxidizing anticancer drug Imexon, respectively.
4.Identification of drugs that restore primary cilium expression in cancer cells.
Khan NA1, Willemarck N1, Talebi A1, Marchand A2, Binda MM1, Dehairs J1, Rueda-Rincon N1, Daniels VW1, Bagadi M1, Raj DB3, Vanderhoydonc F1, Munck S4,5, Chaltin P2,6, Swinnen JV1. Oncotarget. 2016 Mar 1;7(9):9975-92. doi: 10.18632/oncotarget.7198.
The development of cancer is often accompanied by a loss of the primary cilium, a microtubule-based cellular protrusion that functions as a cellular antenna and that puts a break on cell proliferation. Hence, restoration of the primary cilium in cancer cells may represent a novel promising approach to attenuate tumor growth. Using a high content analysis-based approach we screened a library of clinically evaluated compounds and marketed drugs for their ability to restore primary cilium expression in pancreatic ductal cancer cells. A diverse set of 118 compounds stimulating cilium expression was identified. These included glucocorticoids, fibrates and other nuclear receptor modulators, neurotransmitter regulators, ion channel modulators, tyrosine kinase inhibitors, DNA gyrase/topoisomerase inhibitors, antibacterial compounds, protein inhibitors, microtubule modulators, and COX inhibitors. Certain compounds also dramatically affected the length of the cilium.