Perspectives of Protein Kinase C (PKC) Inhibitors as Anti-Cancer Agents

Gonelli, Arianna; Mischiati, Carlo; Guerrini, Remo; Voltan, Rebecca; Salvadori, Severo; Zauli, Giorgio

doi:10.2174/138955709787847967

Cited by 45 publications

(34 citation statements)

References 99 publications

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“…Since our previous data suggested that HMI-1a3 induces PKC-dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in HeLa and SH-SY5Y cells (Gonelli et al, 2009;Talman et al, 2013), we investigated the roles of PKC and ERK1/2 pathways in HMI-1a3-induced cytotoxicity, cell elongation and antiproliferative effects by using pharmacological tools. Inhibition of PKC by the pan-PKC inhibitor Gö6983, activation of PKC by PMA, or MEK inhibition by U0126 were unable to protect HeLa cells from HMI-1a3-induced toxicity (Fig.…”

Section: Effects Of Pharmacological Modulation Of Pkc or The Erk1/2 Pmentioning

confidence: 99%

Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

Talman

Gateva

Ahti

et al. 2014

European Journal of Pharmaceutical Sciences

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Diacylglycerol (DAG) is a central mediator of signaling pathways that regulate cell proliferation, survival and apoptosis. Therefore, C1 domain, the DAG binding site within protein kinase C (PKC) and other DAG effector proteins, is considered a potential cancer drug target. Derivatives of 5-(hydroxymethyl)isophthalic acid are a novel group of C1 domain ligands with antiproliferative and differentiation-inducing effects. Our previous work showed that these isophthalate derivatives exhibit antiproliferative and elongation-inducing effects in HeLa human cervical cancer cells. In this study we further characterized the effects of bis(3-trifluoromethylbenzyl) 5-(hydroxymethyl)isophthalate (HMI-1a3) on HeLa cell proliferation and morphology. HMI-1a3-induced cell elongation was accompanied with loss of focal adhesions and actin stress fibers, and exposure to HMI-1a3 induced a prominent relocation of cofilin-1 into the nucleus regardless of cell phenotype. The antiproliferative and morphological responses to HMI-1a3 were not modified by coexposure to pharmacological inhibition or activation of PKC, or by RNAi knock-down of specific PKC isoforms, suggesting that the effects of HMI-1a3 were not mediated by PKC. Genome-wide gene expression microarray and gene set enrichment analysis suggested that, among others, HMI-1a3 induces changes in small GTPasemediated signaling pathways. Our experiments revealed that the isophthalates bind also to the C1 domains of β2-chimaerin, protein kinase D (PKD) and MRCK, which are potential mediators of small GTPase signaling and cytoskeletal reorganization. Pharmacological inhibition of MRCK, but not that of PKD attenuated HMI1a3-induced cell elongation, suggesting that MRCK participates in mediating the effects of HMI-1a3 on HeLa cell morphology.

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Section: Effects Of Pharmacological Modulation Of Pkc or The Erk1/2 Pmentioning

confidence: 99%

Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

Talman

Gateva

Ahti

et al. 2014

European Journal of Pharmaceutical Sciences

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“…Serine/threonine protein kinase C (PKC) is also involved in malignant transformation, but an anti-PKC approach in cancer therapy has been hampered by the difficulties in developing pharmacological compounds able to selectively inhibit specific PKC isoforms [12]. Gonelli and colleagues [12] reviewed the roles of PKC-epsilon and PKC-delta in promoting and counteracting tumor progression in different types of cancer, along with promising therapeutic perspectives based on small molecule inhibitors of synthetic as well as natural origin.…”

Section: Kinases and Cancermentioning

confidence: 99%

“…Gonelli and colleagues [12] reviewed the roles of PKC-epsilon and PKC-delta in promoting and counteracting tumor progression in different types of cancer, along with promising therapeutic perspectives based on small molecule inhibitors of synthetic as well as natural origin.…”

Section: Kinases and Cancermentioning

confidence: 99%

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

Lamoral-Theys¹,

Pottier

Dufrasne³

et al. 2010

CMC

124

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Over eleven hundred publications reporting anticancer activities of polyphenols have appeared in the peerreviewed literature. In addition, a search of the PubMed database using "polyphenols -cancer -review" as keywords produced over 320 hits for review articles (July 2009). Polyphenol anticancer activities include, among others, anti-oxidative, pro-apoptotic, DNA damaging, anti-angiogenic, and immunostimulatory effects. Targeting specific protein kinases to combat cancer represents a major focus of oncology research within the so-called targeted therapy approach. An exhaustive search of the PubMed database (July 2009) using "polyphenols -cancer -kinases" as keywords resulted in more than 130 hits, half of them having been published within the past five years. Furthermore, the PubMed database contains 25 reviews on the subject of anti-kinase activity of some specific polyphenols, including mainly curcumin and the green tea polyphenol (-)-epigallocatechin 3-gallate (EGCG). However, no attempt has been made yet to review this area of research in a comprehensive, general manner. The current review therefore aims to highlight those anticancer polyphenols that target specific kinases in various types of cancer. The present review also provides an in-depth analysis of polyphenol structure-activity relationships in relation to their anticancer activities and specific kinase targeting. Lastly, a number of polyphenols are identified as potential antitumor agents that could be used to combat biologically aggressive cancers, including metastasizing cancers, through the targeting of specific kinases.

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“…PKCD is involved in pro-and anti-tumoral functions depending on the tumor type (137). miR-181 inhibits proliferation and invasion of A2780 cells and is down-regulated in EOC tissues in comparison to normal tissues (136).…”

Section: Other Eoc-related Metastasis-suppressing Mirsmentioning

confidence: 99%

Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis

Weidle

Birzele

Kollmorgen

et al. 2018

CGP

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Perspectives of Protein Kinase C (PKC) Inhibitors as Anti-Cancer Agents

Cited by 45 publications

References 99 publications

Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3

Natural Polyphenols that Display Anticancer Properties through Inhibition of Kinase Activity

Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis

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