Alkyl cinnamates as regulator for the C1 domain of protein kinase C isoforms

Mamidi, Narsimha; Gorai, Sukhamoy; Sahoo, Jashobanta; Manna, Debasis

doi:10.1016/j.chemphyslip.2012.02.010

Cited by 23 publications

(36 citation statements)

References 38 publications

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“…Design, synthesis, molecular docking, and in vitro ligand-binding analyses of a series of alkyl cinnamates (Figure 1) indicate that these compounds strongly interact with the PKC C1b subdomain [13]. Here, we have investigated the ability of these alkyl cinnamates to cause PKC translocation and affect downstream signaling to disturb cell cycle and cellular viability of breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Alkyl Cinnamates Induce Protein Kinase C Translocation and Anticancer Activity against Breast Cancer Cells through Induction of the Mitochondrial Pathway of Apoptosis

et al. 2016

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PurposeThe protein kinase C (PKC) family of serine-threonine kinases plays an important role in cancer cell progression. Thus, molecules that target PKC have potential as anticancer agents. The current study aims to understand the treatment of breast cancer cells with alkyl cinnamates. We have also explored the mechanistic details of their anticancer action and the underlying molecular signaling.Methods3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to measure the viability of MDAMB-231 breast cancer cells to assess the anticancer activity of these compounds. In addition, flow cytometry was performed to study the effect of alkyl cinnamates on the cell cycle and apoptosis. Immunoblotting and immunofluorescence techniques were performed to study PKC translocation, cytochrome c release, and modulation of the mitochondrial membrane potential in breast cancer cells targeted with alkyl cinnamates.ResultsThe PKC agonist DM-2-8 translocated 16.6%±1.7% PKCα from cytosol to the plasma membrane and showed excellent anticancer activity with an half maximal inhibitory concentration (IC50) of 4.13±0.27 µg/mL against cancer cells. The treated cells had an abnormal morphology and exhibited cell cycle defects with G2/M arrest and reduced S phase. Cancer cells treated with DM-2-3, DM-2-4, or DM-2-8 underwent apoptosis as the major pathway of cell death, further confirmed by genomic DNA fragmentation. Furthermore, the mitochondrial membrane potential was perturbed, indicating involvement of the mitochondrial pathway of apoptosis. Immunolocalization studies revealed cytochrome c release from mitochondria to cytosol. Cancer cells treated with DM-2-8 and curcumin showed activation of caspase-9 and caspase-3 as downstream molecular components of the apoptotic pathway. Alkyl cinnamates also caused oxidative stress, which regulates the apoptotic machinery (DNA fragmentation), cell death, and morphological abnormalities in cancer cells.ConclusionAlkyl cinnamates specifically target cancer cells through induction of PKC translocation and the mitochondrial pathway of apoptosis, and could be promising anticancer drugs.

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Section: Introductionmentioning

confidence: 99%

Alkyl Cinnamates Induce Protein Kinase C Translocation and Anticancer Activity against Breast Cancer Cells through Induction of the Mitochondrial Pathway of Apoptosis

et al. 2016

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“…3 for the H-bond donating phenylic protons. In addition to most of the protein targets mentioned in the preceding section, histone deacetylase 8 (Bora-Tatar et al, 2009) and protein kinase C (PKC)d (Majhi et al, 2010;Mamidi et al, 2012) (section III.E.6) have been identified as cancer-pertinent proteins with which curcumin associates as a result of phenylic hydroxyl group-mediated H-bonding.…”

Section: A Curcumin Structure: Implications On Intermolecular Interamentioning

confidence: 99%

“…References used in Fig. 3: [1] (Yoo and Medina-Franco, 2011); [2] (Muthenna et al, 2009);[5] (Milacic et al, 2008); [9] (Ngo and Li, 2012); [10] ; [11] (Majhi et al, 2010); [12] (Mamidi et al, 2012); [13] (Das et al, 2011);[15] (Bustanji et al, 2009). The data set has been included in Supplemental Table 1. 230 distances between curcumin and several amino acid residues ($2.7 Å), indicating that the metal-diketone interaction is quite significant in the binding of curcumin to HIV-1 integrase.…”

Section: H-bond Accepting Capacity Of the Methoxy Groupsmentioning

confidence: 99%

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Golen²,

et al. 2013

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“…Inhibition of PI(4,5)P 2 /PLCδ1-PH domain interaction by the compounds was further determined by liposome pull-down assay according to the reported procedures [26] , [38] , [39] Liposomes of PC/PE/PS (60:20:20) and PC/PE/PS/PI(4,5)P 2 and PC/PE/PS/PI(3,4,5)P 3 (57:20:20:3) in 50 mM Tris buffer, pH 7.4, containing 150 mM NaCl, 170 mM sucrose, pH 7.4 buffer solution were prepared by sonication, followed by extrusion through 0.1 mm pore size polycarbonate filters. The suspension was pelleted down at 100,000 g , 4 °C, for 20 min and resuspended in binding buffer (20 mM Tris buffer, pH 7.4, containing 100 mM KCl, 5 mM MgCl 2 ).…”

Section: Experimental Methodsmentioning

confidence: 99%

“…However, development of inhibitors for PIP/PH-domain interactions to regulate enzyme activities had not been substantially described yet. Using the similar hypothesis, we recently demonstrated that development of DAG-responsive C1 domain based activator can be considered as an alternative target to regulate the activities of the PKC enzymes [25] , [26] , [27] Recently developed PH-domain targeting lipid-based compound, 3-deoxy phosphatidylinositol ether lipid (DPIEL) and PHT-427 were described as potential drug candidates for the treatment of cancer and other human diseases [21] , [28] Small molecules like PITENINs were also demonstrated as the inhibitor of PI(3,4,5)P 3 binding of AKT1/PDK1-PH-domains and down-regulator of PI3-Kinase/PDK1/AKT1 pathways [8]. There are only a few PLC regulators that play a significant role in understanding the PI(4,5)P 2 mediated cellular signaling pathways [17] , [29] Neomycin is known as a regulator of PI(4,5)P 2 –PLC enzyme interactions and PLC induced PI(4,5)P 2 hydrolysis at the cellular membranes.…”

Section: Introductionmentioning

confidence: 92%

Insights into the inhibitory mechanism of triazole-based small molecules on phosphatidylinositol-4,5-bisphosphate binding pleckstrin homology domain

Gorai

Bagdi

Borah

et al. 2015

Biochemistry and Biophysics Reports

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BackgroundPhosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is an important regulator of several cellular processes and a precursor for other second messengers which are involved in cell signaling pathways. Signaling proteins preferably interact with PI(4,5)P2 through its pleckstrin homology (PH) domain. Efforts are underway to design small molecule-based antagonist, which can specifically inhibit the PI(4,5)P2/PH-domain interaction to establish an alternate strategy for the development of drug(s) for phosphoinositide signaling pathways.MethodsSurface plasmon resonance, molecular docking, circular dichroism, competitive Förster resonance energy transfer, isothermal titration calorimetric analyses and liposome pull down assay were used.ResultsIn this study, we employed 1,2,3-triazol-4-yl methanol containing small molecule (CIPs) as antagonists for PI(4,5)P2/PH-domain interaction and determined their inhibitory effect by using competitive-surface plasmon resonance analysis (IC50 ranges from 53 to 159 nM for PI(4,5)P2/PLCδ1-PH domain binding assay). We also used phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2], PI(4,5)P2 specific PH-domains to determine binding selectivity of the compounds. Various physicochemical analyses showed that the compounds have weak affect on fluidity of the model membrane but, strongly interact with the phospholipase C δ1 (PLCδ1)-PH domains. The 1,2,3-triazol-4-yl methanol moiety and nitro group of the compounds are essential for their exothermic interaction with the PH-domains. Potent compound can efficiently displace PLCδ1-PH domain from plasma membrane to cytosol in A549 cells.ConclusionsOverall, our studies demonstrate that these compounds interact with the PIP-binding PH-domains and inhibit their membrane recruitment.General significanceThese results suggest specific but differential binding of these compounds to the PLCδ1-PH domain and emphasize the role of their structural differences in binding parameters. These triazole-based compounds could be directly used/further developed as potential inhibitor for PH domain-dependent enzyme activity.

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Alkyl cinnamates as regulator for the C1 domain of protein kinase C isoforms

Cited by 23 publications

References 38 publications

Alkyl Cinnamates Induce Protein Kinase C Translocation and Anticancer Activity against Breast Cancer Cells through Induction of the Mitochondrial Pathway of Apoptosis

Alkyl Cinnamates Induce Protein Kinase C Translocation and Anticancer Activity against Breast Cancer Cells through Induction of the Mitochondrial Pathway of Apoptosis

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Insights into the inhibitory mechanism of triazole-based small molecules on phosphatidylinositol-4,5-bisphosphate binding pleckstrin homology domain

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