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A novel synthetic analog of 5, 8-disubstituted quinazolines blocks mitosis and induces apoptosis of tumor cells by inhibiting microtubule polymerization.

Tian W, Qin L, Song Q, He L, Ai M, Jin Y, Zhou Z, You S, Long Y, Yu Q - PLoS ONE (2010)

Bottom Line: Tremendous efforts have been made to identify new anti-mitosis compounds for developing more effective and less toxic anti-cancer drugs.In addition, LJK-11 had synergistic effect with another microtubule inhibitor colchicine on blocking mitosis, but not with vinblastine or nocodazole.Understanding the function and mechanism of LJK-11 will help us to better understand the action of anti-microtubule agents and to design better anti-cancer drugs.

View Article: PubMed Central - PubMed

Affiliation: The School of Life Science and Biopharmaceutics of Shenyang Pharmaceutical University, Liaoning, China.

ABSTRACT
Many mitosis inhibitors are powerful anticancer drugs. Tremendous efforts have been made to identify new anti-mitosis compounds for developing more effective and less toxic anti-cancer drugs. We have identified LJK-11, a synthetic analog of 5, 8-disubstituted quinazolines, as a novel mitotic blocker. LJK-11 inhibited growth and induced apoptosis of many different types of tumor cells. It prevented mitotic spindle formation and arrested cells at early phase of mitosis. Detailed in vitro analysis demonstrated that LJK-11 inhibited microtubule polymerization. In addition, LJK-11 had synergistic effect with another microtubule inhibitor colchicine on blocking mitosis, but not with vinblastine or nocodazole. Therefore, LJK-11 represents a novel anti-microtubule structure. Understanding the function and mechanism of LJK-11 will help us to better understand the action of anti-microtubule agents and to design better anti-cancer drugs.

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Related in: MedlinePlus

Effects of LJK-11 on tubulin structure in non-mitotic cells.A549 cells were incubated on glass coverslips with (B) or without (A) LJK-11 for 4 hours, and then fixed and stained with α-tubulin antibody to visualize microtubules (green) and with DAPI to visualize chromosomes (blue). The cells were visualized by indirect immunofluorescent microscopy.
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pone-0010499-g007: Effects of LJK-11 on tubulin structure in non-mitotic cells.A549 cells were incubated on glass coverslips with (B) or without (A) LJK-11 for 4 hours, and then fixed and stained with α-tubulin antibody to visualize microtubules (green) and with DAPI to visualize chromosomes (blue). The cells were visualized by indirect immunofluorescent microscopy.

Mentions: Most of the anti-mitotic agents interact with microtubules[22]. The effect of LJK-11 on microtubule structure was then examined by immuno-fluorescence microscopy using an α-tubulin antibody. Normal control cells in metaphase displayed a bipolar mitotic spindle. Condensed chromosomes lined up between the spindle poles to form the metaphase plate (Fig. 6A). Cells exposed to LJK-11 for 16 hours displayed disrupted appearance of mitotic spindles (Fig. 6B). To compare the effect of LJK-11 with other mitotic blockers, cells were treated with different concentrations of nocodazole, taxol or colchicine for 16 hours. Taxol, a microtubule-stabilizing agent, increased microtubules and induced multi-polar spindles (Fig. 6E)[23]. Colchicine and nocodazole, two microtubule depolymerizing agents[24], [25], caused multipolar mitotic spindle formation (Fig. 6C and D). LJK-11 (Fig. 6B) also caused multipolar mitotic spindle formation, similar to that of colchicines and nocodazole, suggesting that LJK-11 is a microtubule depolymerizing agent. Further more, the microtubule structure in interphase cells were also disrupted (Fig. 7), further confirming that LJK-11 interacted with tubulin directly.


A novel synthetic analog of 5, 8-disubstituted quinazolines blocks mitosis and induces apoptosis of tumor cells by inhibiting microtubule polymerization.

Tian W, Qin L, Song Q, He L, Ai M, Jin Y, Zhou Z, You S, Long Y, Yu Q - PLoS ONE (2010)

Effects of LJK-11 on tubulin structure in non-mitotic cells.A549 cells were incubated on glass coverslips with (B) or without (A) LJK-11 for 4 hours, and then fixed and stained with α-tubulin antibody to visualize microtubules (green) and with DAPI to visualize chromosomes (blue). The cells were visualized by indirect immunofluorescent microscopy.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2864768&req=5

pone-0010499-g007: Effects of LJK-11 on tubulin structure in non-mitotic cells.A549 cells were incubated on glass coverslips with (B) or without (A) LJK-11 for 4 hours, and then fixed and stained with α-tubulin antibody to visualize microtubules (green) and with DAPI to visualize chromosomes (blue). The cells were visualized by indirect immunofluorescent microscopy.
Mentions: Most of the anti-mitotic agents interact with microtubules[22]. The effect of LJK-11 on microtubule structure was then examined by immuno-fluorescence microscopy using an α-tubulin antibody. Normal control cells in metaphase displayed a bipolar mitotic spindle. Condensed chromosomes lined up between the spindle poles to form the metaphase plate (Fig. 6A). Cells exposed to LJK-11 for 16 hours displayed disrupted appearance of mitotic spindles (Fig. 6B). To compare the effect of LJK-11 with other mitotic blockers, cells were treated with different concentrations of nocodazole, taxol or colchicine for 16 hours. Taxol, a microtubule-stabilizing agent, increased microtubules and induced multi-polar spindles (Fig. 6E)[23]. Colchicine and nocodazole, two microtubule depolymerizing agents[24], [25], caused multipolar mitotic spindle formation (Fig. 6C and D). LJK-11 (Fig. 6B) also caused multipolar mitotic spindle formation, similar to that of colchicines and nocodazole, suggesting that LJK-11 is a microtubule depolymerizing agent. Further more, the microtubule structure in interphase cells were also disrupted (Fig. 7), further confirming that LJK-11 interacted with tubulin directly.

Bottom Line: Tremendous efforts have been made to identify new anti-mitosis compounds for developing more effective and less toxic anti-cancer drugs.In addition, LJK-11 had synergistic effect with another microtubule inhibitor colchicine on blocking mitosis, but not with vinblastine or nocodazole.Understanding the function and mechanism of LJK-11 will help us to better understand the action of anti-microtubule agents and to design better anti-cancer drugs.

View Article: PubMed Central - PubMed

Affiliation: The School of Life Science and Biopharmaceutics of Shenyang Pharmaceutical University, Liaoning, China.

ABSTRACT
Many mitosis inhibitors are powerful anticancer drugs. Tremendous efforts have been made to identify new anti-mitosis compounds for developing more effective and less toxic anti-cancer drugs. We have identified LJK-11, a synthetic analog of 5, 8-disubstituted quinazolines, as a novel mitotic blocker. LJK-11 inhibited growth and induced apoptosis of many different types of tumor cells. It prevented mitotic spindle formation and arrested cells at early phase of mitosis. Detailed in vitro analysis demonstrated that LJK-11 inhibited microtubule polymerization. In addition, LJK-11 had synergistic effect with another microtubule inhibitor colchicine on blocking mitosis, but not with vinblastine or nocodazole. Therefore, LJK-11 represents a novel anti-microtubule structure. Understanding the function and mechanism of LJK-11 will help us to better understand the action of anti-microtubule agents and to design better anti-cancer drugs.

Show MeSH
Related in: MedlinePlus