Artificial Analogs of Naturally Occurring Tumor Promoters as Biochemical Tools and Therapeutic Leads

Nakagawa, Yu

doi:10.1271/bbb.120162

Cited by 21 publications

(14 citation statements)

References 85 publications

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“…The mechanism of TPA reactivation of EBV has also been studied in depth (24, 27, 28). TPA first activates PKC and within 30 minutes triggers p38MAPK kinase phosphorylation (29), resulting in upregulation of MAPK pathway.…”

Section: Resultsmentioning

confidence: 99%

Identification of a New Class of Small Molecules That Efficiently Reactivate Latent Epstein–Barr Virus

et al. 2014

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Epstein-Barr Virus (EBV) persists as a latent infection in many lymphoid and epithelial malignancies, including Burkitt's lymphomas, nasopharyngeal carcinomas, and gastric carcinomas. Current chemotherapeutic treatments of EBV-positive cancers include broad- spectrum cytotoxic drugs that ignore the EBV-positive status of tumors. An alternative strategy, referred to as oncolytic therapy, utilizes drugs that stimulate reactivation of latent EBV to enhance the selective killing of EBV positive tumors, especially in combination with existing inhibitors of herpesvirus lytic replication, like Ganciclovir (GCV). At present, no small molecule, including histone deacetylase (HDAC) inhibitors, have proven safe or effective in clinical trials for treatment of EBV positive cancers. Aiming to identify new chemical entities that induce EBV lytic cycle, we have developed a robust high throughput cell-based assay to screen 66,840 small molecule compounds. Five structurally related tetrahydrocarboline derivatives were identified, two of which had EC50 measurements in the range of 150-170 nM. We show that these compounds reactivate EBV lytic markers ZTA and EA-D in all EBV-positive cell lines we have tested independent of the type of latency. The compounds reactivate a higher percentage of latently infected cells than HDAC inhibitors or phorbol esters in many cell types. The most active compounds showed low toxicity to EBV-negative cells, but were highly effective at selective cell killing of EBV-positive cells when combined with GCV. We conclude that we have identified a class of small molecule compounds that are highly effective at reactivating latent EBV infection in a variety of cell types, and show promise for lytic therapy in combination with GCV.

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Section: Resultsmentioning

confidence: 99%

Identification of a New Class of Small Molecules That Efficiently Reactivate Latent Epstein–Barr Virus

et al. 2014

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“…Protein kinase C (PKC) is a major signaling enzymes that regulates a variety of cell processes including proliferation, apoptosis, cell survival and migration (1)(2)(3). In addition, several oncogenes, such as RAS, FOS, MYC and PKC cooperate during transformation, indicating the involvement of PKC in tumorigenesis (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Aurora kinases are essential for PKC-induced invasion and matrix metalloproteinase-9 expression in MCF-7 breast cancer cells

et al. 2015

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The Aurora kinase family of serine/threonine kinases are known to be crucial for cell cycle control. Aurora kinases are considered a target of anticancer drugs. However, few studies have assessed the effect of Aurora kinases in breast cancer. In the present study, to determine whether Aurora kinases play a role in oncogenic actions of protein kinase C (PKC), we investigated the effect of Aurora kinases on PKC-induced invasion and MMP-9 expression using breast cancer cells. Treatment of MCF-7 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced the upregulation and phosphorylation of Aurora kinases via the MAPK signaling pathway. Moreover, the inhibition of Aurora kinases by their siRNAs and inhibitors suppressed TPA-induced cell invasion and expression of MMP-9 by inhibiting the activation of NF-κB/AP-1, major transcription factors for MMP-9 expression in MCF-7 cells. These results suggested that Aurora kinases mediate PKC-MAPK signal to NF-κB/AP-1 with increasing MMP-9 expression and invasion of MCF-7 cells. To the best of our knowledge, this is the first study to show that Aurora kinases are key molecules in PKC-induced invasion in breast cancer cells.

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“…Due to its importance in cellular signal transduction pathways, PKC is a potential drug target for the treatment of various diseases, particularly in cancer therapy [10]. Researches from Japan recently developed new simplified analogues based on aplysiatoxin class of molecules, e.g., aplog-1, with potent anti-proliferative properties as potential anticancer agents [11,12,13,14,15,16,17,18,19]. These synthetic analogues have been shown to inhibit the action of tumor promotors as well as prevent growth of cancer cells in similar ways to bryostatin 1 [11].…”

Section: Introductionmentioning

confidence: 99%

Anti-Chikungunya Viral Activities of Aplysiatoxin-Related Compounds from the Marine Cyanobacterium Trichodesmium erythraeum

et al. 2014

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Tropical filamentous marine cyanobacteria have emerged as a viable source of novel bioactive natural products for drug discovery and development. In the present study, aplysiatoxin (1), debromoaplysiatoxin (2) and anhydrodebromoaplysiatoxin (3), as well as two new analogues, 3-methoxyaplysiatoxin (4) and 3-methoxydebromoaplysiatoxin (5), are reported for the first time from the marine cyanobacterium Trichodesmium erythraeum. The identification of the bloom-forming cyanobacterial strain was confirmed based on phylogenetic analysis of its 16S rRNA sequences. Structural determination of the new analogues was achieved by extensive NMR spectroscopic analysis and comparison with NMR spectral data of known compounds. In addition, the antiviral activities of these marine toxins were assessed using Chikungunya virus (CHIKV)-infected cells. Post-treatment experiments using the debrominated analogues, namely compounds 2, 3 and 5, displayed dose-dependent inhibition of CHIKV when tested at concentrations ranging from 0.1 µM to 10.0 µM. Furthermore, debromoaplysiatoxin (2) and 3-methoxydebromoaplysiatoxin (5) exhibited significant anti-CHIKV activities with EC50 values of 1.3 μM and 2.7 μM, respectively, and selectivity indices of 10.9 and 9.2, respectively.

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Artificial Analogs of Naturally Occurring Tumor Promoters as Biochemical Tools and Therapeutic Leads

Cited by 21 publications

References 85 publications

Identification of a New Class of Small Molecules That Efficiently Reactivate Latent Epstein–Barr Virus

Identification of a New Class of Small Molecules That Efficiently Reactivate Latent Epstein–Barr Virus

Aurora kinases are essential for PKC-induced invasion and matrix metalloproteinase-9 expression in MCF-7 breast cancer cells

Anti-Chikungunya Viral Activities of Aplysiatoxin-Related Compounds from the Marine Cyanobacterium Trichodesmium erythraeum

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