Indanocine, a Microtubule-Binding Indanone and a Selective Inducer of Apoptosis in Multidrug-Resistant Cancer Cells

Leoni, Lorenzo M.; Hamel, Ernest; Genini, Davide; Shih, Hsiencheng; Carrera, Carlos J.; Cottam, Howard B.; Carson, Dennis A.

doi:10.1093/jnci/92.3.217

Cited by 114 publications

(69 citation statements)

References 25 publications

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“…[46] Therefore, A549 cells were treated with 11 x (0.5 and 1 mm) for 24 h. The results demonstrated a well-organized microtubular network in control cells. However, cells treated with 11 x and nocodozole showed disrupted microtubule organization as seen in Figure 5, thus confirming the inhibition of tubulin polymerization.…”

Section: Immunohistochemistry Studies On Tubulinmentioning

confidence: 89%

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

et al. 2014

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A series of chalcone conjugates featuring the imidazo[2,1-b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF-7, A549, HeLa, DU-145 and HT-29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 μM. Among them, (E)-3-(6-(4-fluorophenyl)-2,3-bis(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)-1-(pyridin-2-yl)prop-2-en-1-one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell-cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase-3, DNA fragmentation analysis, and Annexin V-FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein.

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Section: Immunohistochemistry Studies On Tubulinmentioning

confidence: 89%

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

et al. 2014

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“…Cells were preincubated for 30 min with either 6 mmol/L methoxyamine (Sigma) or 50 Amol/L O 6 -benzylguanine (Sigma), inhibitors of Ape-1 base excision repair enzyme, or alkylguanyl transferase enzyme, respectively. The cells were then exposed to various concentrations of the test materials for 72 h. Cytotoxicity was evaluated by the MTT viability assay (29) and an IC 50 was determined as the drug concentration that inhibited by 50% the viability value of the untreated control. Analyses were done using GraphPad Prism version 3.00 GraphPad Software.…”

Section: Nci Antitumor Screen (Ivclsp)mentioning

confidence: 99%

Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents

Leoni¹,

Bailey

Reifert

et al. 2008

Clinical Cancer Research

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321

318

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Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds. Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard. Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. Conclusion: These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.

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“…Indanocine exhibits toxicity towards multidrug-resistant cell lines. 100 Modeling data provides an explanation to the resistance imparted on indanosine-tubulin interaction upon making Table V. Nocodazole is a potent inhibitor of tubulin polymerization.…”

Section: C O L C H I C I N E S I T E a G E N T S A S A N T I -C Amentioning

confidence: 99%

Anti‐mitotic activity of colchicine and the structural basis for its interaction with tubulin

Bhattacharyya

Panda

Gupta

et al. 2007

Medicinal Research Reviews

434

319

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In this review, an attempt has been made to throw light on the mechanism of action of colchicine and its different analogs as anti-cancer agents. Colchicine interacts with tubulin and perturbs the assembly dynamics of microtubules. Though its use has been limited because of its toxicity, colchicine can still be used as a lead compound for the generation of potent anti-cancer drugs. Colchicine binds to tubulin in a poorly reversible manner with high activation energy. The binding interaction is favored entropically. In contrast, binding of its simple analogs AC or DAAC is enthalpically favored and commences with comparatively low activation energy. Colchicine-tubulin interaction, which is normally pH dependent, has been found to be independent of pH in the presence of microtubule-associated proteins, salts or upon cleavage of carboxy termini of tubulin. Biphasic kinetics of colchicines-tubulin interaction has been explained in light of the variation in the residues around the drug-binding site on beta-tubulin. Using the crystal structure of the tubulin-DAMAcolchicine complex, a detailed discussion on the pharmacophore concept that explains the variation of affinity for different colchicine site inhibitors (CSI) has been discussed.

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Indanocine, a Microtubule-Binding Indanone and a Selective Inducer of Apoptosis in Multidrug-Resistant Cancer Cells

Abstract: The sensitivity of stationary multidrug-resistant cancer cells to indanocine suggests that indanocine and related indanones be considered as lead compounds for the development of chemotherapeutic strategies for drug-resistant malignancies.

Cited by 114 publications

References 25 publications

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents

Anti‐mitotic activity of colchicine and the structural basis for its interaction with tubulin

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