Disease relevance of monastrol

• Furthermore, HR22C16 along with its analogs, inhibit cell survival in both Taxol-sensitive and -resistant ovarian cancer cells with at least 15-fold greater efficacy than monastrol, the first generation Eg5 inhibitor [1].
• Monastrol (1a) and the thio-derivatives 3a, 4a and 6a displayed relevant antiproliferative properties with 3,4-methylenedioxy derivative 6a being approximately more than 30 times more potent than monastrol (1a) against colon cancer (HT-29) cell line [2].

Psychiatry related information on monastrol

• Eg5 distribution in spindles was not perturbed by inhibition of its motor activity with monastrol, but was perturbed by inhibition of dynactin with p50 dynamitin [3].

High impact information on monastrol

• One compound, here named monastrol, arrested mammalian cells in mitosis with monopolar spindles [4].
• A structural model for monastrol inhibition of dimeric kinesin Eg5 [5].
• In contrast, there was a substantial monastrol effect on dimeric Eg5-513, which reduced microtubule lattice decoration [5].
• In addition, upon monastrol removal, centrosomes established a transient chromosome-free bipolar array whose orientation specified the axis along which chromosomes segregated [6].
• Kinetochore fibers (K-fibers) were frequently observed forming in association with chromosomes both during monastrol treatment and after monastrol removal [6].

Biological context of monastrol

• Monastrol is thus a useful tool to study mitotic processes, detection and correction of chromosome malorientation, and contributions of Eg5 to spindle assembly and maintenance [7].
• Chromosomes in monastrol-treated cells frequently have both sister kinetochores attached to microtubules extending to the center of the monoaster (syntelic orientation) [7].
• We find that monastrol does not inhibit progression through S and G2 phases of the cell cycle or centrosome duplication [7].
• Hesperadin also causes cells arrested by taxol or monastrol to enter anaphase within <1 h, whereas cells in nocodazole stay arrested for 3-5 h [8].
• Surprisingly, we identified the (R)-enantiomer bound in the active site, and not, as for monastrol, the (S)-enantiomer [9].

Anatomical context of monastrol

• In HeLa cells, inhibition of KSP by small-molecule inhibitor monastrol resulted in mitotic arrest and rapid caspase activation [10].
• Differential effects of monastrol in two human cell lines [11].
• Here we studied the effects of monastrol, an allosteric HsEg5 inhibitor, on AGS and HT29 cell lines and compared them to those of taxol [11].
• Monastrol retarded oocyte maturation by significantly (P < 0.05) decreasing germinal vesicle breakdown and increasing the frequencies of arrested metaphase I oocytes [12].
• After 3 days, immature neurons treated with monastrol had longer dendrites but slightly shorter axons than control [13].

Gene context of monastrol

• Experiments with monopolar spindles that are induced by the kinesin inhibitor Monastrol indicate that Plk1 is required for the assembly of spindles that are able to generate poleward pulling forces [14].
• In contrast, sensitivity to clinically relevant drugs like taxol or monastrol that inhibit the generation of tension across kinetochores is not modulated by partial downregulation of MAD1, suggesting a functional bifurcation of spindle checkpoint dependent apoptotic pathways [15].
• Monastrol-treated Eg5 also shows a decreased relative affinity for microtubules under equilibrium conditions [16].
• Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein [17].
• KIFC5A knockdown partly rescues the phenotype caused by inhibition of plus-end-directed motor Eg5 by monastrol on the mitotic spindle, indicating that it is involved in the balance of forces determining bipolar spindle assembly and integrity [18].

Analytical, diagnostic and therapeutic context of monastrol

• Stopped-flow fluorometry indicates that monastrol inhibits ADP release by forming an Eg5-ADP-monastrol ternary complex [19].
• This first direct dissection of inhibitor-protein interactions, using these methods, demonstrates a clear disparity in the structural consequences of monastrol in the presence of ADP versus ATP [20].
• Large-scale resolution of racemic monastrol has been carried out by normal-phase mode HPLC on an amylose-based chiral stationary phase [21].
• Here, we used time-lapse video microscopy and biochemical analysis to study the effect of spindle checkpoint abrogation on the response of HeLa cells to monastrol, a selective Eg5 inhibitor [22].

References