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Cell Proliferation Mar 2019The aim of this study was to elucidate the antimitotic mechanism of zerumbone and to investigate its effect on the HeLa cells in combination with other mitotic blockers.
OBJECTIVES
The aim of this study was to elucidate the antimitotic mechanism of zerumbone and to investigate its effect on the HeLa cells in combination with other mitotic blockers.
MATERIALS AND METHODS
HeLa cells and fluorescence microscopy were used to analyse the effect of zerumbone on cancer cell lines. Cellular internalization of zerumbone was investigated using FITC-labelled zerumbone. The interaction of zerumbone with tubulin was characterized using fluorescence spectroscopy. The Chou and Talalay equation was used to calculate the combination index.
RESULTS
Zerumbone selectively inhibited the proliferation of HeLa cells with an IC of 14.2 ± 0.5 μmol/L through enhanced cellular uptake compared to the normal cell line L929. It induced a strong mitotic block with cells exhibiting bipolar spindles at the IC and monopolar spindles at 30 μmol/L. Docking analysis indicated that tubulin is the principal target of zerumbone. In vitro studies indicated that it bound to goat brain tubulin with a Kd of 4 μmol/L and disrupted the assembly of tubulin into microtubules. Zerumbone and colchicine had partially overlapping binding site on tubulin. Zerumbone synergistically enhanced the anti-proliferative activity of vinblastine and paclitaxel through augmented mitotic block.
CONCLUSION
Our data suggest that disruption of microtubule assembly dynamics is one of the mechanisms of the anti-cancer activity of zerumbone and it can be used in combination therapy targeting cell division.
Topics: Antimitotic Agents; Antineoplastic Agents, Phytogenic; Cell Proliferation; Drug Synergism; HeLa Cells; Humans; Mitosis; Neoplasms; Paclitaxel; Sesquiterpenes; Tubulin; Vinblastine
PubMed: 30525278
DOI: 10.1111/cpr.12558 -
Cancer Letters Mar 2019We previously demonstrated that some N-biphenylanilides caused cell-cycle arrest at G2/M transition in breast cancer cells. Among them we choose three derivatives,...
We previously demonstrated that some N-biphenylanilides caused cell-cycle arrest at G2/M transition in breast cancer cells. Among them we choose three derivatives, namely PTA34, PTA73 and RS35 for experimentation in solid tumor cell lines, classical Hodgkin Lymphoma (cHL) cell lines and bona fide normal cell lines. Almost all tumor cells were sensitive to compounds in the nanomolar range whereas, they were not cytotoxic to normal ones. Interestingly the compounds caused a strong G2/M phase arrest in cHL cell lines, thus, here we investigated whether they affected the integrity of microtubules in such cells. We found that they induced a long prometaphase arrest, followed by induction of apoptosis which involved mitochondria. PTA73 and RS35 induced the mitotic arrest through the fragmentation of microtubules which prevented the kinethocore-mitotic spindle interaction and the exit from mitosis. PTA34 is instead a tubulin-targeting agent because it inhibited the tubulin polymerization as vinblastine. As such, PTA34 maintained the Cyclin B1-CDK1 regulatory complex activated during the G2/M arrest while inducing the inactivation of Bcl-2 through phosphorylation in Ser70, the degradation of Mcl-1 and a strong activation of BIML and BIMS proapoptotic isoforms. In addition PTA34 exerted an antiangiogenic effect by suppressing microvascular formation.
Topics: Antimitotic Agents; Biphenyl Compounds; CDC2 Protein Kinase; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin B1; Gene Expression Regulation, Neoplastic; Hodgkin Disease; Humans; Membrane Potential, Mitochondrial; Mitochondria; Molecular Structure; Nicotine; Prometaphase
PubMed: 30583077
DOI: 10.1016/j.canlet.2018.12.013 -
Expert Opinion on Emerging Drugs Mar 2013Mitosis is the key event of the cell cycle, and microtubules play an important part in an array of cellular functions besides mitosis, including maintenance of cell... (Review)
Review
INTRODUCTION
Mitosis is the key event of the cell cycle, and microtubules play an important part in an array of cellular functions besides mitosis, including maintenance of cell shape, cell locomotion, and the movement of intracellular organelles. Various anti-microtubule agents interfere with normal progression of mitosis, such as taxanes and vinca alkaloids. These compounds are widely used in the treatment of advanced non-small cell lung cancer (NSCLC), but their use has been limited by toxicity profile (hematologic and not), acquired resistance, and hypersensitivity reactions.
AREAS COVERED
Recently innovative drug carrier such as nanoparticle showed to reduce toxicity and improve drugs' efficacy. Nanoparticle albumin-bound (nab)-paclitaxel has been recently approved for the use in breast and NSCLC with very promising results in pancreatic adenocarcinoma. Furthermore, the identification of novel mitotic drug targets other than microtubules has gained recently much attention, such as aurora kinases, Polo-like kinase1 (PLK1), kinesin spindle protein (KSP), and centromeric protein E (CENPE).
EXPERT OPINION
Despite recent advances in treatment, NSCLC continues to be the leading cause of cancer death worldwide. Novel agents that target the spindle microtubule elements of mitosis, as well as those that target the non-microtubule effectors of mitosis, are under investigation.
Topics: Animals; Antimitotic Agents; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drugs, Investigational; Humans; Lung Neoplasms; Tubulin Modulators
PubMed: 23448156
DOI: 10.1517/14728214.2013.777426 -
Investigative Ophthalmology & Visual... Aug 2013To investigate the effect of poly (lactic-co-glycolic acid) (PLGA) implants loaded with mitomycin C (MMC) and with different adjuvant treatments after glaucoma... (Comparative Study)
Comparative Study
PURPOSE
To investigate the effect of poly (lactic-co-glycolic acid) (PLGA) implants loaded with mitomycin C (MMC) and with different adjuvant treatments after glaucoma filtration surgery (GFS), in comparison to standard treatments.
METHODS
Forty-two New Zealand White rabbits underwent bilateral GFS and received different treatments: topical MMC (group 1); topical 5-fluorouracil (5-FU; group 2); PLGA implant (group 3); MMC-loaded and -coated PLGA implant (group 4); MMC-loaded and 5-FU-coated PLGA implant (group 5); subconjunctival bevacizumab (group 6); MMC-loaded PLGA implant and subconjunctival bevacizumab (group 7); and no treatment (right eye of all animals; control group). Intraocular pressure (IOP) and filtering bleb were evaluated on different days after GFS. Histology was performed to examine the conjunctiva, sclerotomy, filtering bleb, and persistence of the implant.
RESULTS
The best hypotensive results were achieved in the MMC-loaded and -coated PLGA implant group, which presented the lowest IOP values on days 1, 5, 7, 14, and 28 after GFS. Excluding the implant groups, in which the bleb could not be properly measured, bleb survival was superior to controls in groups 1, 2 and lower in group 6. Group 7 presented greater extension, height, and vascularization of the bleb. Epithelial thinning and lymphoplasmacytic infiltrate were observed in groups 1, 2, 4, 5, and 7. The rates of closure of the sclerotomy and bleb were 100% and 76%, respectively, and implant persistence was 95%.
CONCLUSIONS
MMC-loaded and -coated implants have optimal surgical results, followed by topical MMC application. In this experimental model, bevacizumab could interact with MMC.
Topics: Animals; Antimitotic Agents; Coated Materials, Biocompatible; Conjunctiva; Disease Models, Animal; Drug Carriers; Female; Glaucoma; Intraocular Pressure; Lactic Acid; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Postoperative Complications; Prostheses and Implants; Rabbits; Trabeculectomy; Treatment Outcome
PubMed: 23800769
DOI: 10.1167/iovs.13-11777 -
Journal of Cell Science Aug 2009In 2007, over 12-million people were diagnosed with cancer. According to the American Cancer Society, at least one third of these individuals are not expected to survive... (Review)
Review
In 2007, over 12-million people were diagnosed with cancer. According to the American Cancer Society, at least one third of these individuals are not expected to survive the disease, making cancer the second most prevalent cause of death worldwide. Systemic chemotherapy forms the mainstay of cancer treatment, and agents that disrupt mitotic spindle assembly - so called ;anti-mitotics' - are commonly used to treat a wide variety of cancers. Traditional anti-mitotic agents include the microtubule toxins such as taxol, other taxanes and the vinca alkaloids, all of which have proven successful in the clinic. However, patient response remains highly unpredictable, and drug resistance is common. In addition, toxicity is a problem. To address these limitations, a new generation of anti-mitotic drugs is being developed. As the first wave of these new agents enters clinical trails, much hope rests on their outcome. Meanwhile, significant attention is being focused on trying to predict which tumour types are likely to respond. In this Commentary, we outline recent advances in our understanding of how cancer cells respond to anti-mitotic drugs, and discuss the relevance of these studies to their use in the clinic.
Topics: Antimitotic Agents; Cell Death; Humans; Mitosis; Neoplasms
PubMed: 19625502
DOI: 10.1242/jcs.039719 -
Organic & Biomolecular Chemistry May 2015A series of 2-anilinopyridyl–triazole conjugates (6a–t) were prepared and evaluated for their cytotoxic activity against a panel of three human cancer cell lines....
A series of 2-anilinopyridyl–triazole conjugates (6a–t) were prepared and evaluated for their cytotoxic activity against a panel of three human cancer cell lines. Among them compounds 6q, 6r and 6s showed significant cytotoxic activity with IC50 values ranging from 0.1 to 4.1 μM. Structure–activity relationships were elucidated with various substitutions on these conjugates. Flow cytometric analysis revealed that these compounds arrest the cell cycle at the G2/M phase and induce cell death by apoptosis. The tubulin polymerization assay and immunofluorescence analysis showed that these compounds (6q, 6r and 6s) effectively inhibited the microtubule assembly in human prostate cancer cells (DU-145). The docking studies showed that 6s interacts and binds efficiently with the tubulin protein at the colchicine binding site. This was further confirmed by the colchicine competitive binding assay. Moreover, compounds 6q, 6r and 6s possess anti-tubulin activity both in vitro and within cells as demonstrated by the ratio of soluble versus polymerized tubulin. Further the apoptotic effects of compounds were confirmed by Hoechst staining, caspase 3 activation, annexin-V FITC, mitochondrial membrane potential and DNA fragmentation analysis. Interestingly, these compounds did not affect the normal human embryonic kidney cells, HEK-293.
Topics: Aminopyridines; Antimitotic Agents; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; HEK293 Cells; HT29 Cells; Humans; Mitochondria; Molecular Docking Simulation; Molecular Structure; Pyrazoles; Structure-Activity Relationship
PubMed: 25765224
DOI: 10.1039/c5ob00232j -
European Journal of Medicinal Chemistry Jul 2013Thorough simplification of vinca alkaloids based on pharmacophore similarity has been conducted. A concise process for the syntheses of target compounds was successfully...
Thorough simplification of vinca alkaloids based on pharmacophore similarity has been conducted. A concise process for the syntheses of target compounds was successfully developed with yields from poor to excellent (19-98%). Cell growth inhibitory activities of these synthesized compounds were evaluated in five cancer cell lines including MCF-7, MDA-MB-231, HepG2, HepG2/ADM and K562. Almost all compounds exhibited moderate antitumor activity with optimal IC50 value of 0.89 ± 0.07 μM in MCF-7 cells. Investigation of structure-activity relationship (SAR) indicates that electron-withdraw substituents on the ring contribute to the enhancement of the antitumor activities. The simplified vinca alkaloids are confirmed as antimitotic agents, which inhibit the polymerization of tubulin just like vinblastine.
Topics: Antimitotic Agents; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; K562 Cells; MCF-7 Cells; Models, Molecular; Molecular Structure; Structure-Activity Relationship; Vinca Alkaloids
PubMed: 23708010
DOI: 10.1016/j.ejmech.2013.04.057 -
Nature Chemical Biology Jan 2006Cell division is the process by which a cell creates two genetically identical daughter cells. To maintain genomic integrity, a complex and highly regulated sequence of... (Review)
Review
Cell division is the process by which a cell creates two genetically identical daughter cells. To maintain genomic integrity, a complex and highly regulated sequence of events ensures that the replicated chromosomes are equally partitioned between the daughter cells. For more than 50 years, strategies designed around small-molecule inhibitors have been critical in advancing our understanding of this essential process. Here we introduce a series of questions on the biology of cell division and illustrate how small molecules have been used to design experiments to address these questions. Because of the highly dynamic nature of cell division, the temporal control over protein function that is possible with small molecules has been particularly valuable in dissecting biological mechanisms.
Topics: Animals; Antimitotic Agents; Cell Division; Chromosomes; Colchicine; Cytokinesis; Humans; Models, Biological; Muscle Spindles; Protein Serine-Threonine Kinases
PubMed: 16408087
DOI: 10.1038/nchembio757 -
Scientific Reports Jun 2016Pancreatic cancer is the leading cause of cancer death worldwide with a poor survival rate. The objective of this study was to determine the mechanism of action of a...
Pancreatic cancer is the leading cause of cancer death worldwide with a poor survival rate. The objective of this study was to determine the mechanism of action of a novel antimitotic and Stat3 inhibitor, LTP-1, on human pancreatic cancer in vitro and in vivo. We found that LTP-1 inhibited pancreatic cancer cell growth and viability with significant G2/M arrest and disruption of microtubule dynamics. LTP-1 also caused G2/M arrest-independent Stat3 dephosphorylation along with ERK activation, which indicated the possible dual function of LTP-1. Long-term treatment of LTP-1 also induced polyploidy, activated caspases, induced subG1 cell population, and therefore, triggered pancreatic cancer cell apoptosis. Finally, we used an in vivo xenograft model to demonstrate that LTP-1 suppressed the growth of pancreatic adenocarcinoma. In summary, our data suggest that LTP-1 may alter microtubule dynamics, which ultimately causes polyploidy and apoptosis, thereby inhibiting pancreatic cancer growth in vitro and in vivo. This study provides evidence that LTP-1 could be a potential therapeutic agent for further development of pancreatic cancer treatment.
Topics: Animals; Antimitotic Agents; Arylsulfonic Acids; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Mice; Pancreatic Neoplasms; Phosphorylation; STAT3 Transcription Factor; Xenograft Model Antitumor Assays
PubMed: 27278358
DOI: 10.1038/srep27794 -
The Journal of Organic Chemistry Nov 2011The spirastrellolides are a family of potent antimitotic agents isolated from the marine sponge Spirastrella coccinea . Synthetic studies toward the DEF bis-spiroacetal...
The spirastrellolides are a family of potent antimitotic agents isolated from the marine sponge Spirastrella coccinea . Synthetic studies toward the DEF bis-spiroacetal core of spirastrellolide B are reported. A modular approach was pursued by the use of two dithiane disconnections to enable a highly convergent synthesis. The ease of lithiation and nucleophilicity of these 2-substituted-1,3-dithianes were investigated during the course of the synthesis, and the alkylations were found to proceed most efficiently at elevated temperatures. Formation of the [5,6,6]-bis-spiroacetal ring system was achieved via a double dithiane deprotection/spiroacetalization strategy.
Topics: Alkylation; Antimitotic Agents; Biological Products; Macrolides; Molecular Structure; Quinolizines; Spiro Compounds; Sulfur Compounds
PubMed: 21995770
DOI: 10.1021/jo201729t