Characterization of the cytotoxic mechanism of Mana-Hox, an analog of manzamine alkaloids.
Mana-Hox is a synthetic analog of manzamines, which are beta-carboline alkaloids isolated from marine sponges. Mana-Hox exhibited cytotoxicity against various tumor cell lines with the IC(50) range from 1 to 5 microM. Cell cycle synchronization and flow cytometric analysis showed that Mana-Hox delayed cell cycle progression at mitosis. At the concentration that delayed mitotic progression, bipolar spindle with lagged chromosomes and multipolar spindle with disorganized chromosomes were detected. The presence of such aberrant mitotic cells accompanied by the activation of spindle checkpoint that delayed cells exit from mitosis. However, after a short delay, lagged chromosomes were able to display in the abnormal metaphase plates, and subsequent cell division resulting in chromosome missegregation. Furthermore, the aberrant mitotic cells showed lower viability, indicating that Mana-Hox-induced cell death resulting from chromosome missegregation. This study is the first to explore cytotoxic mechanism of a manzamine-related compound and understand its potential as a lead compound for the development of future anticancer agents.
Tu
Lan Chun
LC
Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan, ROC.
Chou
Chen-Kung
CK
Chen
Ching-Yeu
CY
Chang
Yao-To
YT
Shen
Ya-Ching
YC
Yeh
Sheau-Farn
SF
D000470:Alkaloids / Q000737:chemistry* / Q000633:toxicity*; D002227:Carbazoles; D002243:Carbolines / Q000737:chemistry* / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000187:drug effects; D003603:Cytotoxins / Q000737:chemistry* / Q000633:toxicity*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry*; D008941:Spindle Apparatus / Q000187:drug effects
D000470:Alkaloids; D002227:Carbazoles; D002243:Carbolines; D003603:Cytotoxins; D007211:Indoles; C487937:Mana-Hox; D011758:Pyrroles; C078290:manzamine A; D015739:Nocodazole