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2 results on '"Hamill BD"'

1. Drug Design Targeting T-Cell Factor-Driven Epithelial-Mesenchymal Transition as a Therapeutic Strategy for Colorectal Cancer.

Author

Abraham AD, Esquer H, Zhou Q, Tomlinson N, Hamill BD, Abbott JM, Li L, Pike LA, Rinaldetti S, Ramirez DA, Lunghofer PJ, Gomez JD, Schaack J, Nemkov T, D'Alessandro A, Hansen KC, Gustafson DL, Messersmith WA, and LaBarbera DV

Subjects
Adenosine Triphosphate metabolism, Animals, Binding, Competitive, Cell Line, Tumor, Colorectal Neoplasms pathology, DNA Topoisomerases, Type II metabolism, Drug Design, Drug Screening Assays, Antitumor, Humans, Mice, Molecular Targeted Therapy, Poly-ADP-Ribose Binding Proteins metabolism, Structure-Activity Relationship, TCF Transcription Factors metabolism, Topoisomerase II Inhibitors pharmacokinetics, Transcription, Genetic, Colorectal Neoplasms drug therapy, Epithelial-Mesenchymal Transition drug effects, TCF Transcription Factors genetics, Topoisomerase II Inhibitors chemistry, Topoisomerase II Inhibitors pharmacology
Abstract

Metastasis is the cause of 90% of mortality in cancer patients. For metastatic colorectal cancer (mCRC), the standard-of-care drug therapies only palliate the symptoms but are ineffective, evidenced by a low survival rate of ∼11%. T-cell factor (TCF) transcription is a major driving force in CRC, and we have characterized it to be a master regulator of epithelial-mesenchymal transition (EMT). EMT transforms relatively benign epithelial tumor cells into quasi-mesenchymal or mesenchymal cells that possess cancer stem cell properties, promoting multidrug resistance and metastasis. We have identified topoisomerase IIα (TOP2A) as a DNA-binding factor required for TCF-transcription. Herein, we describe the design, synthesis, biological evaluation, and in vitro and in vivo pharmacokinetic analysis of TOP2A ATP-competitive inhibitors that prevent TCF-transcription and modulate or reverse EMT in mCRC. Unlike TOP2A poisons, ATP-competitive inhibitors do not damage DNA, potentially limiting adverse effects. This work demonstrates a new therapeutic strategy targeting TOP2A for the treatment of mCRC and potentially other types of cancers.

Published
2019
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2. An improved high yield total synthesis and cytotoxicity study of the marine alkaloid neoamphimedine: an ATP-competitive inhibitor of topoisomerase IIα and potent anticancer agent.

Author

Li L, Abraham AD, Zhou Q, Ali H, O'Brien JV, Hamill BD, Arcaroli JJ, Messersmith WA, and LaBarbera DV

Subjects
Acid Phosphatase metabolism, Antigens, Neoplasm drug effects, Antigens, Neoplasm metabolism, Apoptosis drug effects, Cell Cycle drug effects, Cell Line, Tumor, DNA Topoisomerases, Type II drug effects, DNA Topoisomerases, Type II metabolism, DNA-Binding Proteins drug effects, DNA-Binding Proteins metabolism, G2 Phase drug effects, Humans, Models, Molecular, Rhodamines chemistry, Acridines chemical synthesis, Acridines pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Topoisomerase II Inhibitors chemical synthesis, Topoisomerase II Inhibitors pharmacology
Abstract

Recently, we characterized neoamphimedine (neo) as an ATP-competitive inhibitor of the ATPase domain of human Topoisomerase IIα. Thus far, neo is the only pyridoacridine with this mechanism of action. One limiting factor in the development of neo as a therapeutic agent has been access to sufficient amounts of material for biological testing. Although there are two reported syntheses of neo, both require 12 steps with low overall yields (≤6%). In this article, we report an improved total synthesis of neo achieved in 10 steps with a 25% overall yield. In addition, we report an expanded cytotoxicity study using a panel of human cancer cell lines, including: breast, colorectal, lung, and leukemia. Neo displays potent cytotoxicity (nM IC50 values) in all, with significant potency against colorectal cancer (lowest IC50 = 6 nM). We show that neo is cytotoxic not cytostatic, and that neo exerts cytotoxicity by inducing G2-M cell cycle arrest and apoptosis.

Published
2014
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