Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones

Cyclin-dependent kinase 6 (CDK6) is a potential drug target that plays an important role in the progression of different types of cancers. We performed in silico and in vitro screening of different natural compounds and found that quercetin has a high binding affinity for the CDK6 and inhibits its activity with an IC 50 = 5.89 μM. Molecular docking and a 200 ns whole atom simulation of the CDK6-quercetin complex provide insights into the binding mechanism and stability of the complex. Binding parameters ascertained by fluorescence and isothermal titration calorimetry studies revealed a binding constant in the range of 10 7 M –1 of quercetin to the CDK6. Thermodynamic parameters associated with the formation of the CDK6–quercetin complex suggested an electrostatic interaction-driven process. The cell-based protein expression studies in the breast (MCF-7) and lung (A549) cancer cells revealed that the treatment of quercetin decreases the expression of CDK6. Quercetin also decreases the viability and colony formation potential of selected cancer cells. Moreover, quercetin induces apoptosis, by decreasing the production of reactive oxygen species and CDK6 expression. Both in silico and in vitro studies highlight the significance of quercetin for the development of anticancer leads in terms of CDK6 inhibitors.

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“…From the final reaction mixture, 100 μL was transferred to a 96-well plate in triplicates to measure spectrophotometrically at 620 nm. 69 …”

Section: Methodsmentioning

confidence: 99%

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

et al. 2020

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“…Cell cultures were routinely cultured and trypsinized not more than 30 passages. To assess the cytotoxic potential of As 3+ , MTT assay was carried out by following previously published protocols 51–53 . Briefly, HEK-293 cells were plated at a seeding density of 9000–10000 cells/well in a 96-well cell culture plate and grown overnight.…”

Section: Methodsmentioning

confidence: 99%

Engineering genetically encoded FRET-based nanosensors for real time display of arsenic (As3+) dynamics in living cells

Soleja

Manzoor

Khan

et al. 2019

Sci Rep

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Arsenic poisoning has been a major concern that causes severe toxicological damages. Therefore, intricate and inclusive understanding of arsenic flux rates is required to ascertain the cellular concentration and establish the carcinogenetic mechanism of this toxicant at real time. The lack of sufficiently sensitive sensing systems has hampered research in this area. In this study, we constructed a fluorescent resonance energy transfer (FRET)-based nanosensor, named SenALiB (Sensor for Arsenic Linked Blackfoot disease) which contains a metalloregulatory arsenic-binding protein (ArsR) as the As 3+ sensing element inserted between the FRET pair enhanced cyan fluorescent protein (ECFP) and Venus. SenALiB takes advantage of the ratiometic FRET readout which measures arsenic with high specificity and selectivity. SenALiB offers rapid detection response, is stable to pH changes and provides highly accurate, real-time optical readout in cell-based assays. SenALiB-676n with a binding constant ( K d ) of 0.676 × 10 −6 M is the most efficient affinity mutant and can be a versatile tool for dynamic measurement of arsenic concentration in both prokaryotes and eukaryotes in vivo in a non-invasive manner.

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“…Molecular docking was carried out while using Autodock Vina and AutoDock 4 package, as described previously [21,22]. Autodock Vina uses an advanced docking algorithm and scoring function of protein ligand interactions.…”

Section: Molecular Dockingmentioning

confidence: 99%

Novel Mechanistic Insight into the Anticancer Activity of Cucurbitacin D against Pancreatic Cancer (Cuc D Attenuates Pancreatic Cancer)

Sikander

Malik

Khan

et al. 2019

Cells

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Pancreatic cancer (PanCa) is one of the leading causes of death from cancer in the United States. The current standard treatment for pancreatic cancer is gemcitabine, but its success is poor due to the emergence of drug resistance. Natural products have been widely investigated as potential candidates in cancer therapies, and cucurbitacin D (Cuc D) has shown excellent anticancer properties in various models. However, there is no report on the therapeutic effect of Cuc D in PanCa. In the present study, we investigated the effects of the Cuc D on PanCa cells in vitro and in vivo. Cuc D inhibited the viability of PanCa cells in a dose and time dependent manner, as evident by MTS assays. Furthermore, Cuc D treatment suppressed the colony formation, arrest cell cycle, and decreased the invasion and migration of PanCa cells. Notably, our findings suggest that mucin 13 (MUC13) is down-regulated upon Cuc D treatment, as demonstrated by Western blot and qPCR analyses. Furthermore, we report that the treatment with Cuc D restores miR-145 expression in PanCa cells/tissues. Cuc D treatment suppresses the proliferation of gemcitabine resistant PanCa cells and inhibits RRM1/2 expression. Treatment with Cuc D effectively inhibited the growth of xenograft tumors. Taken together, Cuc D could be utilized as a novel therapeutic agents for the treatment/sensitization of PanCa.

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Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by N-Substituted Acridones

Cited by 54 publications

References 50 publications

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

Engineering genetically encoded FRET-based nanosensors for real time display of arsenic (As3+) dynamics in living cells

Novel Mechanistic Insight into the Anticancer Activity of Cucurbitacin D against Pancreatic Cancer (Cuc D Attenuates Pancreatic Cancer)

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