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S9, a novel anticancer agent, exerts its anti-proliferative activity by interfering with both PI3K-Akt-mTOR signaling and microtubule cytoskeleton.

Zhang C, Yang N, Yang CH, Ding HS, Luo C, Zhang Y, Wu MJ, Zhang XW, Shen X, Jiang HL, Meng LH, Ding J - PLoS ONE (2009)

Bottom Line: S9 possessed inhibitory activity against both PI3K and mTOR with little effect on other tested 30 kinases.Further study revealed that S9 inhibited tubulin polymerization via binding to colchicine-binding site of tubulin and resulted in microtubule disturbance.Taken together, S9 targets both PI3K-Akt-mTOR signaling and microtubule cytoskeleton, which combinatorially contributes its antitumor activity and provides new clues for anticancer drug design and development.

View Article: PubMed Central - PubMed

Affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT

Background: Deregulation of the phosphatidylinositol 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway plays a central role in tumor formation and progression, providing validated targets for cancer therapy. S9, a hybrid of alpha-methylene-gamma-lactone and 2-phenyl indole compound, possessed potent activity against this pathway.

Methodology/principal findings: Effects of S9 on PI3K-Akt-mTOR pathway were determined by Western blot, immunofluorescence staining and in vitro kinas assay. The interactions between tubulin and S9 were investigated by polymerization assay, CD, and SPR assay. The potential binding modes between S9 and PI3K, mTOR or tubulin were analyzed by molecular modeling. Anti-tumor activity of S9 was evaluated in tumor cells and in nude mice bearing human cancer xenografts. S9 abrogated EGF-activated PI3K-Akt-mTOR signaling cascade and Akt translocation to cellular membrane in human tumor cells. S9 possessed inhibitory activity against both PI3K and mTOR with little effect on other tested 30 kinases. S9 also completely impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. S9 unexpectedly arrested cells in M phase other than G1 phase, which was distinct from compounds targeting PI3K-Akt-mTOR pathway. Further study revealed that S9 inhibited tubulin polymerization via binding to colchicine-binding site of tubulin and resulted in microtubule disturbance. Molecular modeling indicated that S9 could potentially bind to the kinase domains of PI3K p110alpha subunit and mTOR, and shared similar hydrophobic interactions with colchicines in the complex with tubulin. Moreover, S9 induced rapid apoptosis in tumor cell, which might reflect a synergistic cooperation between blockade of both PI3-Akt-mTOR signaling and tubulin cytoskeleton. Finally, S9 displayed potent antiproliferative activity in a panel of tumor cells originated from different tissue types including drug-resistant cells and in nude mice bearing human tumor xenografts.

Conclusions/significance: Taken together, S9 targets both PI3K-Akt-mTOR signaling and microtubule cytoskeleton, which combinatorially contributes its antitumor activity and provides new clues for anticancer drug design and development.

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Related in: MedlinePlus

The binding mode of S9 within tubulin.The protein is represented by cartoon. The residues interacting with the compounds are shown in sticks. S9 and colchicine are also represented by sticks and colored in cyan and yellow, respectively. All of the structural diagrams were prepared using PyMOL (http://pymol.sourceforge.net).
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pone-0004881-g005: The binding mode of S9 within tubulin.The protein is represented by cartoon. The residues interacting with the compounds are shown in sticks. S9 and colchicine are also represented by sticks and colored in cyan and yellow, respectively. All of the structural diagrams were prepared using PyMOL (http://pymol.sourceforge.net).

Mentions: The superimposed binding models of S9 and colchicine in tubulin were next performed (Fig. 5). Despite their strikingly difference in structures, the conformation of S9 occupies similar Cartesian space in the colchicine site. Moreover, S9 hydrophobically interacts with Val 181, Cys 241, Val 318, Lys 352 and Ile 378, which interact similarly with colchicine. Of particular note, the MOMO group, lying in the side chain of the phenylindole, formed a hydrogen bond with Lys 254, which might offer a conformation for S9 to place effectively in tubulin. In contrast, S7, in which MOMO group is replaced by H [8], has no effect on tubulin polymerization (data not shown).


S9, a novel anticancer agent, exerts its anti-proliferative activity by interfering with both PI3K-Akt-mTOR signaling and microtubule cytoskeleton.

Zhang C, Yang N, Yang CH, Ding HS, Luo C, Zhang Y, Wu MJ, Zhang XW, Shen X, Jiang HL, Meng LH, Ding J - PLoS ONE (2009)

The binding mode of S9 within tubulin.The protein is represented by cartoon. The residues interacting with the compounds are shown in sticks. S9 and colchicine are also represented by sticks and colored in cyan and yellow, respectively. All of the structural diagrams were prepared using PyMOL (http://pymol.sourceforge.net).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654064&req=5

pone-0004881-g005: The binding mode of S9 within tubulin.The protein is represented by cartoon. The residues interacting with the compounds are shown in sticks. S9 and colchicine are also represented by sticks and colored in cyan and yellow, respectively. All of the structural diagrams were prepared using PyMOL (http://pymol.sourceforge.net).
Mentions: The superimposed binding models of S9 and colchicine in tubulin were next performed (Fig. 5). Despite their strikingly difference in structures, the conformation of S9 occupies similar Cartesian space in the colchicine site. Moreover, S9 hydrophobically interacts with Val 181, Cys 241, Val 318, Lys 352 and Ile 378, which interact similarly with colchicine. Of particular note, the MOMO group, lying in the side chain of the phenylindole, formed a hydrogen bond with Lys 254, which might offer a conformation for S9 to place effectively in tubulin. In contrast, S7, in which MOMO group is replaced by H [8], has no effect on tubulin polymerization (data not shown).

Bottom Line: S9 possessed inhibitory activity against both PI3K and mTOR with little effect on other tested 30 kinases.Further study revealed that S9 inhibited tubulin polymerization via binding to colchicine-binding site of tubulin and resulted in microtubule disturbance.Taken together, S9 targets both PI3K-Akt-mTOR signaling and microtubule cytoskeleton, which combinatorially contributes its antitumor activity and provides new clues for anticancer drug design and development.

View Article: PubMed Central - PubMed

Affiliation: Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT

Background: Deregulation of the phosphatidylinositol 3-kinases (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway plays a central role in tumor formation and progression, providing validated targets for cancer therapy. S9, a hybrid of alpha-methylene-gamma-lactone and 2-phenyl indole compound, possessed potent activity against this pathway.

Methodology/principal findings: Effects of S9 on PI3K-Akt-mTOR pathway were determined by Western blot, immunofluorescence staining and in vitro kinas assay. The interactions between tubulin and S9 were investigated by polymerization assay, CD, and SPR assay. The potential binding modes between S9 and PI3K, mTOR or tubulin were analyzed by molecular modeling. Anti-tumor activity of S9 was evaluated in tumor cells and in nude mice bearing human cancer xenografts. S9 abrogated EGF-activated PI3K-Akt-mTOR signaling cascade and Akt translocation to cellular membrane in human tumor cells. S9 possessed inhibitory activity against both PI3K and mTOR with little effect on other tested 30 kinases. S9 also completely impeded hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin. S9 unexpectedly arrested cells in M phase other than G1 phase, which was distinct from compounds targeting PI3K-Akt-mTOR pathway. Further study revealed that S9 inhibited tubulin polymerization via binding to colchicine-binding site of tubulin and resulted in microtubule disturbance. Molecular modeling indicated that S9 could potentially bind to the kinase domains of PI3K p110alpha subunit and mTOR, and shared similar hydrophobic interactions with colchicines in the complex with tubulin. Moreover, S9 induced rapid apoptosis in tumor cell, which might reflect a synergistic cooperation between blockade of both PI3-Akt-mTOR signaling and tubulin cytoskeleton. Finally, S9 displayed potent antiproliferative activity in a panel of tumor cells originated from different tissue types including drug-resistant cells and in nude mice bearing human tumor xenografts.

Conclusions/significance: Taken together, S9 targets both PI3K-Akt-mTOR signaling and microtubule cytoskeleton, which combinatorially contributes its antitumor activity and provides new clues for anticancer drug design and development.

Show MeSH
Related in: MedlinePlus