Drug-resistant T-lymphoid tumors undergo apoptosis selectively in response to an antimicrotubule agent, EM011.
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, such as 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 complete blood count profiles. These findings suggest that EM011 may be a safe and effective chemotherapeutic agent for oral treatment of drug-resistant human lymphomas.
Aneja
Ritu
R
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Zhou
Jun
J
Vangapandu
Surya N
SN
Zhou
Binfei
B
Chandra
Ramesh
R
Joshi
Harish C
HC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005260:Female; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects; D015996:Survival Rate; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004149:Dioxoles; C510553:EM011 compound; D007546:Isoquinolines