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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

Effect of LJK-11 on tyrosine phosphorylation of signaling proteins.A549 cells were treated with 50 µM LJK-11 for 6, 12, 24, or 36 hours. The cell lysates were resolved by SDS-PAGE and analyzed by Western bolt analysis using antibodies as indicated. Antibodies specific to the phosphorylated forms of the indicated proteins are labeled with (-P).
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pone-0010499-g004: Effect of LJK-11 on tyrosine phosphorylation of signaling proteins.A549 cells were treated with 50 µM LJK-11 for 6, 12, 24, or 36 hours. The cell lysates were resolved by SDS-PAGE and analyzed by Western bolt analysis using antibodies as indicated. Antibodies specific to the phosphorylated forms of the indicated proteins are labeled with (-P).

Mentions: To explore the mechanism of the growth inhibition and cell death effects of LJK-11 on tumor cells, we analyzed the expression and phosphorylation of several major cell growth and survival signaling proteins along the tyrosine kinase signaling pathway, including ERK, JNK, and AKT. The results indicated that LJK-11 had no obvious effect on the phosphorylation of JNK, but increased the phosphorylation of ERK 1/2 and decreased the phosphorylation of AKT (Fig. 4), suggesting that inhibition of the PI3K/AKT pathway may be one of the mechanisms that responsible for the LJK-11-induced growth arrest and/or cell death.


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)

Effect of LJK-11 on tyrosine phosphorylation of signaling proteins.A549 cells were treated with 50 µM LJK-11 for 6, 12, 24, or 36 hours. The cell lysates were resolved by SDS-PAGE and analyzed by Western bolt analysis using antibodies as indicated. Antibodies specific to the phosphorylated forms of the indicated proteins are labeled with (-P).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0010499-g004: Effect of LJK-11 on tyrosine phosphorylation of signaling proteins.A549 cells were treated with 50 µM LJK-11 for 6, 12, 24, or 36 hours. The cell lysates were resolved by SDS-PAGE and analyzed by Western bolt analysis using antibodies as indicated. Antibodies specific to the phosphorylated forms of the indicated proteins are labeled with (-P).
Mentions: To explore the mechanism of the growth inhibition and cell death effects of LJK-11 on tumor cells, we analyzed the expression and phosphorylation of several major cell growth and survival signaling proteins along the tyrosine kinase signaling pathway, including ERK, JNK, and AKT. The results indicated that LJK-11 had no obvious effect on the phosphorylation of JNK, but increased the phosphorylation of ERK 1/2 and decreased the phosphorylation of AKT (Fig. 4), suggesting that inhibition of the PI3K/AKT pathway may be one of the mechanisms that responsible for the LJK-11-induced growth arrest and/or cell death.

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