Non‐toxic melanoma therapy by a novel tubulin‐binding agent
Open Access
- 22 July 2009
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 126 (1), 256-265
- https://doi.org/10.1002/ijc.24765
Abstract
(S)‐3‐((R)‐9‐bromo‐4‐methoxy‐6‐methyl‐5,6,7,8‐tetrahydro‐[1,3]dioxolo[4,5‐g]isoquino‐lin‐5‐yl)‐6,7‐dimethoxyisobenzofuran‐1(3H)‐one (EM011) is a tubulin‐binding agent with significant anticancer activity. Here we show that EM011 modulates microtubule dynamics at concentrations that do not alter the total polymer mass of tubulin. In particular, EM011 decreases the transition frequencies between growth and shortening phases and increases the duration microtubules spend in an idle ‘pause’ state. Using B16LS9 murine melanoma cells, we show that EM011 briefly arrests cell‐cycle progression at the G2/M phase by formation of multiple aster spindles. An aberrant mitotic exit without cytokinesis then occurs, leading to the accumulation of abnormal multinucleated cells prior to apoptosis. Our pharmacokinetic studies conformed to a linear dose‐response relationship upto 150 mg/kg. However, non‐linearity was observed at 300 mg/kg. In a syngeneic murine model of subcutaneous melanoma, better antitumor responses were seen at 150 mg/kg compared to 300 mg/kg of EM011. Unlike currently available chemotherapeutics, EM011 is non‐toxic to normal tissues and most importantly, does not cause any immunosuppression and neurotoxicity. Our data thus warrant a clinical evaluation of EM011 for melanoma therapy.Keywords
This publication has 32 references indexed in Scilit:
- Multidrug Resistance-Associated Protein–Overexpressing Teniposide-Resistant Human Lymphomas Undergo Apoptosis by a Tubulin-Binding AgentCancer Research, 2008
- Spatiotemporal localization of injury potentials in DRG neurons during vincristine-induced axonal degenerationNeuroscience Letters, 2007
- Complex Combination Biochemotherapy Regimen in Advanced Metastatic Melanoma in a Non-intensive Care Unit: Toxicity or Benefit?Japanese Journal of Clinical Oncology, 2007
- Treatment of hormone-refractory breast cancer: apoptosis and regression of human tumors implanted in miceMolecular Cancer Therapeutics, 2006
- Evidence for direct axonal toxicity in vincristine neuropathyJournal of the Peripheral Nervous System, 2006
- Malignant melanoma: genetics and therapeutics in the genomic eraGenes & Development, 2006
- Wlds mice are resistant to paclitaxel (taxol) neuropathyAnnals of Neurology, 2002
- Classical chemotherapy for metastatic melanomaClinical and Experimental Dermatology, 2000
- The chemoresistance of human malignant melanomaMelanoma Research, 1999
- New Colorimetric Cytotoxicity Assay for Anticancer-Drug ScreeningJNCI Journal of the National Cancer Institute, 1990