NMK-BH2, a novel microtubule-depolymerising bis (indolyl)-hydrazide-hydrazone, induces apoptotic and autophagic cell death in cervical cancer cells by binding to tubulin at colchicine – site

Mukherjee, Dipanwita Das; Kumar, Nikhil; Tantak, Mukund P.; Datta, Satabdi; Dastidar, Debabrata Ghosh; Kumar, Dalip; Chakrabarti, Gopal

doi:10.1016/j.bbamcr.2020.118762

Cited by 17 publications

(11 citation statements)

References 81 publications

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“…The decreased cell killing effect, observed when autophagosome formation was inhibited by 3MA, demonstrated that blockage of autophagosome traffic and the accumulation of autophagosomes promotes paclitaxel-induced cancer cell death [ 144 ]. In line with these findings, several new tubulin binding agents have been shown to activate apoptosis as a result of autophagic flux inhibition in cancer cells [ 145 , 146 , 147 , 148 ]. It could be envisaged that induction of autophagosome formation in response to prolonged mitotic arrest and/or mitotic slippage, together with the reduction of autophagosome turnover by flux blockage, could result in the accumulation of autophagosomes, the intracellular persistence of toxic substances and/or damaged organelles, the production of oxygen reactive species, and cytotoxicity [ 149 ].…”

Section: Autophagy–microtubule Crosstalk As a Possible Target For Cancer Growth Controlmentioning

confidence: 76%

The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer

Trisciuoglio

Degrassi

2021

Cancers

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Microtubules are tubulin polymers that constitute the structure of eukaryotic cells. They control different cell functions that are often deregulated in cancer, such as cell shape, cell motility and the intracellular movement of organelles. Here, we focus on the crucial role of tubulin modifications in determining different cancer characteristics, including metastatic cell migration and therapy resistance. We also discuss the influence of microtubule modifications on the autophagic process—the cellular degradation pathway that influences cancer growth. We discuss findings showing that inducing microtubule modifications can be used as a means to kill cancer cells by inhibiting autophagy.

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Section: Autophagy–microtubule Crosstalk As a Possible Target For Cancer Growth Controlmentioning

confidence: 76%

The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer

Trisciuoglio

Degrassi

2021

Cancers

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“…In this experiment, Autodock Vina software [ 27 ] was used for molecular docking simulation. AutoDockTools 1.5.6 [ 28 ] is used to prepare all input files. PDB-IDs of target genes were obtained from Protein Data Bank (PDB) [ 29 ] database.…”

Section: Methodsmentioning

confidence: 99%

Identification of Diagnostic Genes and Effective Drugs Associated with Osteoporosis Treatment by Single-Cell RNA-Seq Analysis and Network Pharmacology

Zhang

Zhou

et al. 2022

Mediators of Inflammation

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Background. Osteoporosis is a common bone metabolic disease with increased bone fragility and fracture rate. Effective diagnosis and treatment of osteoporosis still need to be explored due to the increasing incidence of disease. Methods. Single-cell RNA-seq was acquired from GSE147287 dataset. Osteoporosis-related genes were obtained from chEMBL. Cell subpopulations were identified and characterized by scRNA-seq, t-SNE, clusterProfiler, and other computational methods. “limma” R packages were used to identify all differentially expressed genes. A diagnosis model was build using rms R packages. Key drugs were determined by proteins-proteins interaction and molecular docking. Results. Firstly, 15,577 cells were obtained, and 12 cell subpopulations were identified by clustering, among which 6 cell subpopulations belong to CD45+ BM-MSCs and the other subpopulations were CD45-BM-MSCs. CD45- BM-MSCs_6 and CD45+ BM-MSCs_5 were consider as key subpopulations. Furthermore, we found 7 genes were correlated with above two subpopulations, and F9 gene had highest AUC. Finally, five compounds were identified, among which DB03742 bound well to F9 protein. Conclusions. This work discovered that 7 genes were correlated with CD45-BM-MSCs_6 and CD45+ BM-MSCs_5 subpopulations in osteoporosis, among which F9 gene had better research value. Moreover, compound DB03742 was a potential inhibitor of F9 protein.

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“…Meanwhile, bis-indole rings extended into a hydrophobic pocket formed by residues GLN 176, TYR 210, ARG 221, PRO 222, MET 325, ASP 329, GLU 330 and LEU 333 (Figure 14B). Based on previous studies [79], a bis(indolyl)-hydrazide-hydrazone derivative NMK-BH2 (31) [80] was identified as a new anti-microtubule drug, and further research was conducted. The results of in vitro anti-proliferative activity showed that compound 31 exhibited a potent efficacy and selectivity against HeLa cells, with an IC50 value of 1.5 ± 0.25 µM, whereas it is negligibly toxic towards normal human cells (Table 3).…”

Section: Bis-indole Derivativesmentioning

confidence: 99%

“…Therefore, the compound 31 was identified and established as a novel microtubule-targeting anti-cancer drug that could be used as a prospective guide for the development of emerging chemotherapeutic drugs. Based on previous studies [79], a bis(indolyl)-hydrazide-hydrazone derivative NMK-BH2 (31) [80] was identified as a new anti-microtubule drug, and further research was conducted. The results of in vitro anti-proliferative activity showed that compound 31 exhibited a potent efficacy and selectivity against HeLa cells, with an IC 50 value of 1.5 ± 0.25 µM, whereas it is negligibly toxic towards normal human cells (Table 3).…”

Section: Bis-indole Derivativesmentioning

confidence: 99%

Indole-Based Tubulin Inhibitors: Binding Modes and SARs Investigations

et al. 2022

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Tubulin inhibitors can interfere with normal cell mitosis and inhibit cell proliferation through interfering with the normal structure and function of microtubules, forming spindle filaments. Indole, as a privileged pharmacological skeleton, has been widely used in anti-cancer inhibitors. A variety of alkaloids containing an indole core obtained from natural sources have been proven to inhibit tubulin polymerization, and an ever-increasing number of synthetic indole-based tubulin inhibitors have been reported. Among these, several kinds of indole-based derivatives, such as TMP analogues, aroylindoles, arylthioindoles, fused indole, carbazoles, azacarbolines, alkaloid nortopsentin analogues and bis-indole derivatives, have shown good inhibition activities towards tubulin polymerization. The binding modes and SARs investigations of synthetic indole derivatives, along with a brief mechanism on their anti-tubulin activity, are presented in this review.

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NMK-BH2, a novel microtubule-depolymerising bis (indolyl)-hydrazide-hydrazone, induces apoptotic and autophagic cell death in cervical cancer cells by binding to tubulin at colchicine – site

Cited by 17 publications

References 81 publications

The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer

The Tubulin Code and Tubulin-Modifying Enzymes in Autophagy and Cancer

Identification of Diagnostic Genes and Effective Drugs Associated with Osteoporosis Treatment by Single-Cell RNA-Seq Analysis and Network Pharmacology

Indole-Based Tubulin Inhibitors: Binding Modes and SARs Investigations

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