FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling

Shafiq, Muhammad; Steinbrecher, Thomas; Schmid, Ralf

doi:10.1371/journal.pone.0042612

Cited by 48 publications

(39 citation statements)

References 86 publications

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“…Crystal structures of STAT3 (PDB:1BG1), PARP (PDB: 1WOK), p38 alpha (PDB: 1OVE), NF-kB (PDB:1VKX), AKT (PDB: 2JDO), CDK6 (PDB: 1X02), mTOR (PDB:4JSP), MKK4 (PDB:3ALN), JAK (PDB:3EYG), BCL-2 (PDB: 2O21), MEK1 (PDB: 3VVH), CHK1 (PDB: 2E9P), PI3K (PDB:3L54), and CHK2 (PDB: 2WTJ) protein structures were retrieved from Protein Data Bank (PDB) and imported to Discovery studio work environment. The structure of CDK4/Cyclin D1 was downloaded from previously reported work [25]. Later, the proteins were prepared by removing HETATM lines other than co-factors and unwanted water molecules from the structure.…”

Section: In-silico Docking Analysismentioning

confidence: 99%

Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways

et al. 2019

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Cardiac glycosides (CGs) are a diverse family of naturally derived compounds having a steroid and glycone moiety in their structures. CG molecules inhibit the α-subunit of ubiquitous transmembrane protein Na+/K+-ATPase and are clinically approved for the treatment of cardiovascular diseases. Recently, the CGs were found to exhibit selective cytotoxic effects against cancer cells, raising interest in their use as anti-cancer molecules. In this current study, we explored the underlying mechanism responsible for the anti-cancer activity of Lanatoside C against breast (MCF-7), lung (A549), and liver (HepG2) cancer cell lines. Using Real-time PCR, western blot, and immunofluorescence studies, we observed that (i) Lanatoside C inhibited cell proliferation and induced apoptosis in cell-specific and dose-dependent manner only in cancer cell lines; (ii) Lanatoside C exerts its anti-cancer activity by arresting the G2/M phase of cell cycle by blocking MAPK/Wnt/PAM signaling pathways; (iii) it induces apoptosis by inducing DNA damage and inhibiting PI3K/AKT/mTOR signaling pathways; and finally, (iv) molecular docking analysis shows significant evidence on the binding sites of Lanatoside C with various key signaling proteins ranging from cell survival to cell death. Our studies provide a novel molecular insight of anti-cancer activities of Lanatoside C in human cancer cells.

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Section: In-silico Docking Analysismentioning

confidence: 99%

Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways

et al. 2019

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“…The marine natural product fascaplysin is known to be one of the most potent cyclin‐dependent kinase 4 (CDK4) specific inhibitors . However, fascaplysin exhibits high toxicities due to its DNA intercalating properties .…”

Section: Tubulin Kinase Dual Inhibition In Anticancer Treatmentmentioning

confidence: 99%

“…The marine natural product fascaplysin is known to be one of the most potent cyclin-dependent kinase 4 (CDK4) specific inhibitors. 150,170 However, fascaplysin exhibits high toxicities due to its DNA intercalating properties. 150,171 As of recent, Mahale et al 150 identified a nonplanar tryptoline analogue, BPT (66), as potent CDK4 D1 enzyme specific inhibitor and did not demonstrate DNA binding properties, primarily due to its planar structure.…”

Section: Cyclin-dependent Kinasementioning

confidence: 99%

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Arnst

Banerjee

Chen

et al. 2019

Medicinal Research Reviews

122

107

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Microtubule (MT)‐targeting agents are highly successful drugs as chemotherapeutic agents, and this is attributed to their ability to target MT dynamics and interfere with critical cellular functions, including, mitosis, cell signaling, intracellular trafficking, and angiogenesis. Because MT dynamics vary in the different stages of the cell cycle, these drugs tend to be the most effective against mitotic cells. While this class of drug has proven to be effective against many cancer types, significant hurdles still exist and include overcoming aspects such as dose limited toxicities and the development of resistance. Newer generations of developed drugs attack these problems and alternative approaches such as the development of dual tubulin and kinase inhibitors are being investigated. This approach offers the potential to show increased efficacy and lower toxicities. This review covers different categories of MT‐targeting agents, recent advances in dual inhibitors, and current challenges for this drug target.

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“…In the sponge, fascaplysin (2) is the major compound which represents 0.02% of the lyophilized sponge weigh. It exhibits many biological activities including cytotoxicity against tumoral cells (Segraves et al 2004;Shafiq et al 2012;Hamilton 2014;Cells et al 2015;Kumar et al 2015), antimicrobial activities (Roll et al 1988), and the inhibition of acetylcholinesterase (Bharate et al 2012;Manda et al 2016). For microbial disease treatments in aquaculture, fascaplysin (2) is not ideal.…”

Section: Fascaplysinmentioning

confidence: 99%

Potential of fascaplysin and palauolide from Fascaplysinopsis cf reticulata to reduce the risk of bacterial infection in fish farming

Mai¹,

Toullec

Wynsberge

et al. 2019

Fish Aquatic Sci

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Marine natural products isolated from the sponge Fascaplysinopsis cf reticulata, in French Polynesia, were investigated as an alternative to antibiotics to control pathogens in aquaculture. The overuse of antibiotics in aquaculture is largely considered to be an environmental pollution, because it supports the transfer of antibiotic resistance genes within the aquatic environment. One environmentally friendly alternative to antibiotics is the use of quorum sensing inhibitors (QSIs). Quorum sensing (QS) is a regulatory mechanism in bacteria which control virulence factors through the secretion of autoinducers (AIs), such as acyl-homoserine lactone (AHL) in gramnegative bacteria. Vibrio harveyi QS is controlled through three parallel pathways: HAI-1, AI-2, and CAI-1. Bioassayguided purification of F. cf reticulata extract was conducted on two bacterial species, i.e., Tenacibaculum maritimum and V. harveyi for antibiotic and QS inhibition bioactivities. Toxicity bioassay of fractions was also evaluated on the freshwater fish Poecilia reticulata and the marine fish Acanthurus triostegus. Cyclohexanic and dichloromethane fractions of F. cf reticulata exhibited QS inhibition on V. harveyi and antibiotic bioactivities on V. harveyi and T. maritimum, respectively. Palauolide (1) and fascaplysin (2) were purified as major molecules from the cyclohexanic and dichloromethane fractions, respectively. Palauolide inhibited QS of V. harveyi through HAI-1 QS pathway at 50 μg ml-1 (26 μM), while fascaplysin affected the bacterial growth of V. harveyi (50 μg ml-1) and T. maritimum (0.25 μg). The toxicity of fascaplysin-enriched fraction (FEF) was evaluated and exhibited a toxic effect against fish at 50 μg ml-1. This study demonstrated for the first time the QSI potential of palauolide (1). Future research may assess the toxicity of both the cyclohexanic fraction of the sponge and palauolide (1) on fish, to confirm their potential as alternative to antibiotics in fish farming.

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FASCAPLYSIN as a Specific Inhibitor for CDK4: Insights from Molecular Modelling

Cited by 48 publications

References 86 publications

Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways

Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

Potential of fascaplysin and palauolide from Fascaplysinopsis cf reticulata to reduce the risk of bacterial infection in fish farming

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