Abstract | PURPOSE: METHODS AND RESULTS: In this study, we describe the characterization of select lead compounds from a novel class of indazole-based tubulin inhibitors. Three lead compounds, TH-337, TH-482 and TH-494, exhibit potent antiproliferative activity against cell lines derived from human pancreatic carcinoma, human breast adenocarcinoma and human colorectal adenocarcinoma cells. The three compounds were also tested for cytotoxicity against a panel of clinically relevant drug resistant cancer cell lines that either overexpress the drug resistance pumps MDR-1, MRP-1 and BCRP-1 or have altered Topoisomerase II activity. TH-482 and -494 retained cytotoxic activities against all of the resistant cell lines tested; however, TH-337 exhibited decreased cytotoxicity in the cell line overexpressing BCRP-1, indicating that TH-337 is a substrate of that pump. We show that TH-482's antiproliferative activity is due to cell cycle arrest at the G(2)/M phase. We demonstrate that TH-482 binds specifically to the colchicine site of tubulin and that it inhibits tubulin polymerization in vitro in a concentration-dependent manner. The in vitro anti-vascular activities of TH-482 were assessed using the HUVEC-C cell line. TH-482 inhibits in vitro neovessel formation and disrupts pre-established vessels using HUVEC-C cells. TH-482 also increases permeability of vascular endothelial cells in a concentration- and time-dependent manner. CONCLUSIONS: TH-482 demonstrates potent in vitro efficacy as a novel tubulin-targeted anti-proliferative and anti-vascular agent and notably is more potent in antiproliferative assays than the benchmark compound combretastatin A-4. These results identify TH-482 as a potent tubulin inhibitor, and support the investigation of its in vivo efficacy and pharmacokinetic properties as the prototype of a new class of anti- tubulin agents.
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Authors | Fanying Meng, Xiaohong Cai, Jianxin Duan, Mark G Matteucci, Charles P Hart |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 61
Issue 6
Pg. 953-63
(May 2008)
ISSN: 0344-5704 [Print] Germany |
PMID | 17639393
(Publication Type: Journal Article)
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Chemical References |
- ABCG2 protein, human
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
- Angiogenesis Inhibitors
- Fluoresceins
- Fluorescent Dyes
- Multidrug Resistance-Associated Proteins
- Neoplasm Proteins
- Tubulin
- Tubulin Modulators
- calcein AM
- DNA Topoisomerases, Type II
- multidrug resistance-associated protein 1
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Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(metabolism)
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
(metabolism)
- Angiogenesis Inhibitors
(pharmacology)
- Calorimetry, Differential Scanning
- Capillary Permeability
(drug effects)
- Cell Cycle
(drug effects)
- Cell Division
(drug effects)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- DNA Topoisomerases, Type II
(metabolism)
- Dose-Response Relationship, Drug
- Fluoresceins
- Fluorescent Dyes
- G2 Phase
(drug effects)
- Humans
- Microscopy, Fluorescence
- Multidrug Resistance-Associated Proteins
(metabolism)
- Neoplasm Proteins
(metabolism)
- Tubulin
(metabolism)
- Tubulin Modulators
(pharmacology)
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