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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2486-2492.
Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-08-3516.
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Submitted August 31, 2005
Accepted October 27, 2005
Drug resistant T-lymphoid tumors apoptose selectively by an antimicrotubule agent, EM011
Ritu Aneja, Jun Zhou, Surya N Vangapandu, Binfei Zhou, Ramesh Chandra, and Harish C Joshi*
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA, USA
Departmemts of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China
BR Ambedkar Center for Biomedical Research, University of Delhi, Delhi, Delhi, India
* Corresponding author; email: joshi{at}cellbio.emory.edu.
We have shown previously that EM011, a synthetic compound, binds tubulin with a higher affinity than the founding compound noscapine without changing total microtubule polymer mass. Now we show that EM011 is potently effective against vinblastine-resistant human lymphoblastoid line CEM/VLB100 and its parental vinblastine-sensitive line CEM. The cytotoxicity is mediated by cell-cycle arrest at G2/M phase and subsequent apoptosis, as indicated by altered plasma membrane asymmetry, loss of mitochondrial transmembrane potential, activation of caspase-3, and increased DNA fragmentation. Furthermore, oral EM011 treatment of nude mice bearing human lymphoma xenografts results in pronounced tumor regression by triggering apoptosis and significantly lengthens the survival time of mice. EM011 treatment does not have obvious side effects in tissues with frequently dividing cells, like the spleen and duodenum. In addition, EM011 does not show any toxicity in the liver, lung, heart, brain, and sciatic nerve. More importantly, EM011 does not affect hematopoiesis as determined by CBC profiles. These findings suggest that EM011 may serve as a safe and effective chemotherapeutic agent for oral treatment of drug-resistant human lymphomas.
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