Interaction of tubulin and cellular microtubules with the new antitumor drug MDL 27048

Peyrot, Vincent; Leynadier, Daniel; Sarrazin, M.; Briand, Claudette; Rodriquez, A; Nieto, Juan Miguel; Andreu, José Manuel

doi:10.1016/s0021-9258(19)30078-x

Cited by 44 publications

(26 citation statements)

References 18 publications

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“…In this regard, DK-chalcone based compounds blocked the proliferation of HER2 positive breast cancer cells ZR75 and SKBR3 by inducing apoptosis, combined with sub G0 phase arrest and S phase blockade. The first study by Peyrot et al, (1989) reported an antimitotic role of chalcones; the group demonstrated that chalcones result in G2/M phase arrest during cell cycle progression [26]. In addition, similar to our data, other studies have reported chalcone targets that induce apoptosis along with hindering cell cycle progression, these mechanisms were mediated by loss of cyclin expression [27,28] or induced expression of p21, an inhibitor of CDKs [28,29].…”

Section: Discussionsupporting

confidence: 88%

Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways

Rizeq

Gupta

Kheraldine

et al. 2021

IJMS

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Natural chalcones possess antitumor properties and play a role as inducers of apoptosis, antioxidants and cytotoxic compounds. We recently reported that novel nitrogen chalcone-based compounds, which were generated in our lab, have specific effects on triple-negative breast cancer cells. However, the outcome of these two new compounds on human epidermal growth factor receptor 2 (HER2)-positive breast cancer remains nascent. Thus, we herein investigated the effects of these compounds (DK-13 and DK-14) on two HER2-positive breast cancer cell lines, SKBR3 and ZR75. Our data revealed that these compounds inhibit cell proliferation, deregulate cell-cycle progression and significantly induce cell apoptosis in both cell lines. Furthermore, the two chalcone compounds cause a significant reduction in the cell invasion ability of SKBR3 and ZR75 cancer cells. In parallel, we found that DK-13 and DK-14 inhibit colony formation of both cell lines in comparison to their matched controls. On the other hand, we noticed that these two compounds can inhibit angiogenesis in the chorioallantoic membrane model. The molecular pathway analysis of chalcone compounds exposed cells revealed that these compounds inhibit the expression of both JNK1/2/3 and ERK1/2, the major plausible molecular pathways behind these events. Our findings implicate that DK-13 and DK-14 possess effective chemotherapeutic outcomes against HER2-positive breast cancer via the ERK1/2 and JNK1/2/3 signaling pathways.

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Section: Discussionsupporting

confidence: 88%

Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways

Rizeq

Gupta

Kheraldine

et al. 2021

IJMS

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“…Tubulin is a dimeric protein consisting of two similar, nonidentical subunits: α and β. The discovery of chalcones as antimitotic agents was first reported nearly 30 years ago [ 134 ]. Based on the understanding of the colchicine-tubulin structure–activity relationship, chalcone derivatives are modeled as colchicine analogs, which can bind to tubulin and prevent its polymerization, leading to abrupt interruption of mitotic spindle assembly, interference with the function of the cytoskeleton, and interrupted mitosis.…”

Section: Representative Mechanisms Of Anticancer Action Of Chalconesmentioning

confidence: 99%

Chalcone Derivatives: Role in Anticancer Therapy

et al. 2021

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Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future applications and scope of the chalcone family toward the treatment and prevention of cancer are brought out.

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“…Colchicine-site drugs inhibit the polymerization of purified tubulin into microtubules. In assays using tubulin from mammalian brain, MDL has been found to inhibit polymerization ( Peyrot et al, 1989 ). Therefore, we polymerized CeTb in the presence of MDL to look for inhibition.…”

Section: Resultsmentioning

confidence: 99%

Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles

Montecinos

Loew²,

Chio³

et al. 2022

Front. Cell Dev. Biol.

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Tubulin, the main component of microtubules, is an α-β heterodimer that contains one of multiple isotypes of each monomer. Although the isotypes of each monomer are very similar, the beta tubulin isotype found in blood cells is significantly divergent in amino acid sequence compared to other beta tubulins. This isotype, beta class VI, coded by human gene TUBB1, is found in hematologic cells and is recognized as playing a role in platelet biogenesis and function. Tubulin from the erythrocytes of the chicken Gallus gallus contains almost exclusively βVI tubulin. This form of tubulin has been reported to differ from brain tubulin in binding of colchicine-site ligands, previously thought to be a ubiquitous characteristic of tubulin from higher eukaryotes. In this study, we sought to gain a better understanding of the structure-activity relationship of the colchicine site of this divergent isotype, using chicken erythrocyte tubulin (CeTb) as the model. We developed a fluorescence-based assay to detect binding of drugs to the colchicine site and used it to study the interaction of 53 colchicine-site ligands with CeTb. Among the ligands known to bind at this site, most colchicine derivatives had lower affinity for CeTb compared to brain tubulin. Remarkably, many of the benzimidazole class of ligands shows increased affinity for CeTb compared to brain tubulin. Because the colchicine site of human βVI tubulin is very similar to that of chicken βVI tubulin, these results may have relevance to the effect of anti-cancer agents on hematologic tissues in humans.

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Interaction of tubulin and cellular microtubules with the new antitumor drug MDL 27048

Cited by 44 publications

References 18 publications

Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways

Novel Nitrogen-Based Chalcone Analogs Provoke Substantial Apoptosis in HER2-Positive Human Breast Cancer Cells via JNK and ERK1/ERK2 Signaling Pathways

Chalcone Derivatives: Role in Anticancer Therapy

Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles

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