Oligomannurarate sulfate, a novel antimitotic agent, exerts anti-cancer activity by binding to tubulin on novel site.
Tubulin-binding agents have received considerable interest as potential anti-cancer drugs. These compounds interfere with tubulin dynamics and microtubule organization and thereby induce cell growth arrest at G(2)/M phase, and eventually lead to apoptotic cell death. Herein, we report that sulfated oligosaccharide JG3 was effective at inhibiting viability of cancer cells, and suppressing tumor growth in vivo. Our studies showed that JG3 significantly arrested cell cycle at G(2)/M phase and led cancer cells to apoptotic death. Consistent with this, tubulin was identified as a binding protein of JG3 using affinity chromatography and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The interaction between JG3 and tubulin was characterized by surface plasmon resonance (SPR) analysis. Furthermore, it was demonstrated both at cellular level and in cell free system that JG3 potently prevented tubulin polymerization, thereby demolished microtubule organization in cancer cells. The underlying mechanism lies in its binding to tubulin on a unique site distinct from other conventional binding sites. All these suggest that JG3 is a novel antimitotic reagent, and this might shed new light on the understanding of anti-cancer activities and mechanisms of novel antimitotic reagents, and help develop new antimitotic agents in cancer therapy.
Miao
Benchun
B
Department of Pharmacology, Marine Drug and Food Institute, Ocean University of China, Qingdao, China.
Chen
Yi
Y
Li
Jing
J
Xin
Xianliang
X
Gan
Li
L
Fu
Xueyan
X
Geng
Meiyu
M
D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D005434:Flow Cytometry; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008351:Mannans / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000302:isolation & purification; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014404:Tubulin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D050256:Antimitotic Agents; D008351:Mannans; D016328:NF-kappa B; D010446:Peptide Fragments; D014404:Tubulin; C524388:oligomannurarate sulfate