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TH induced mitotic arrest is leading to asymmetric cell division and cell death. (A) Quantitative analysis of images acquired by time-lapse microscopy (Olympus IX81, 10 £ , 1 image/5 min for 24 h) showed that TH and vinblastine significantly increased the time HeLa-H2B-GFP cells spent in mitosis (left panel). The cell fate (bipolar division, asymmetric division or apoptosis) was quantitatively assessed after 24 h of treatment (right panel, n D 2, mean § SD). Representative images of cells treated with TH (2.5 mM) and DMSO. Black arrows indicate cells displaying signs of asymmetric division and fusion. Red arrows point at cells dying. Scale bar D 20 mm. (B) Tracking of cell fate of cells that underwent asymmetric division. Representative image of HeLa-H2B-GFP cells treated with TH (2.5 mM) and tracked for 106 h using real-time live-cell imaging (IncuCyte 10 £ , 1 image/2 h for 144 h). White arrows indicate cells going through asymmetric division, fusion and dying in mitosis. Red arrows mark cells that die in an interphase-like state after 2 consecutive rounds of asymmetric division separated by a cell fusion event. Yellow arrows indicate cells going through asymmetric division, fusion and dying in an interphase-like state. Scale bar D 50 mm. For more details, see Videos 1-3.
Source publication
We report for the first time the mechanism of action of the natural product thalicthuberine (TH) in prostate and cervical cancer cells. TH induced a strong accumulation of LNCaP cells in mitosis, severe mitotic spindle defects and asymmetric cell divisions, ultimately leading to mitotic catastrophe accompanied by cell death through apoptosis. Howev...
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... 32. cells that underwent anaphases with completed karyokinesis and cytokinesis (into 3 or more daughter cells) frequently fused into single multinuclear cells (Fig. 4A, Videos S1-S3). 30 A simi- lar phenomenon was observed when HeLa cells were treated with vinblastine (Video S1, Fig. 4A). Furthermore, the cell fate of asymmetrically divided HeLa- H2B-GFP after TH treatment was analyzed by time-lapse microscopy. As depicted in Fig. 4B, some first generation daughter cells derived from asymmetric divisions died in an interphase-like state without entering another round of divi- sion, whereas other daughter cells died during the next cell cycle round, or went through another round of asymmetric division, after which second generation offspring failed to divide further and died in an interphase-like ...
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... 32. cells that underwent anaphases with completed karyokinesis and cytokinesis (into 3 or more daughter cells) frequently fused into single multinuclear cells (Fig. 4A, Videos S1-S3). 30 A simi- lar phenomenon was observed when HeLa cells were treated with vinblastine (Video S1, Fig. 4A). Furthermore, the cell fate of asymmetrically divided HeLa- H2B-GFP after TH treatment was analyzed by time-lapse microscopy. As depicted in Fig. 4B, some first generation daughter cells derived from asymmetric divisions died in an interphase-like state without entering another round of divi- sion, whereas other daughter cells died during the next cell cycle round, or went through another round of asymmetric division, after which second generation offspring failed to divide further and died in an interphase-like ...
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... 32. cells that underwent anaphases with completed karyokinesis and cytokinesis (into 3 or more daughter cells) frequently fused into single multinuclear cells (Fig. 4A, Videos S1-S3). 30 A simi- lar phenomenon was observed when HeLa cells were treated with vinblastine (Video S1, Fig. 4A). Furthermore, the cell fate of asymmetrically divided HeLa- H2B-GFP after TH treatment was analyzed by time-lapse microscopy. As depicted in Fig. 4B, some first generation daughter cells derived from asymmetric divisions died in an interphase-like state without entering another round of divi- sion, whereas other daughter cells died during the next cell cycle round, or went through another round of asymmetric division, after which second generation offspring failed to divide further and died in an interphase-like ...
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... better characterize TH-mediated mitotic arrest, we stud- ied the time cells required for completion of mitosis and fate of mitosis-arrested cells using time-lapse microscopy of HeLa cells expressing H2B-GFP (Fig. 4A). DMSO-treated HeLa cells normally progressed through mitosis with a mean time of ...
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... melting temperature and displacement of a fluorescent DNA intercalator in a titration experiment with TH ( Supplementary Fig. S2A) In order to better characterize TH-mediated mitotic arrest, we studied the time cells required for completion of mitosis and fate of mitosis-arrested cells using time-lapse microscopy of HeLa cells expressing H2B-GFP (Fig. 4A). DMSO-treated HeLa cells normally progressed through mitosis with a mean time of 67.4 ± 32.4 min, followed by cytokinesis (87.1% bipolar division leading to two daughter cells, Fig. 4A). Furthermore, the cell fate of asymmetrically divided HeLa-H2B-GFP after TH treatment was analyzed by time-lapse microscopy. As depicted in Figure 4B, ...
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... we studied the time cells required for completion of mitosis and fate of mitosis-arrested cells using time-lapse microscopy of HeLa cells expressing H2B-GFP (Fig. 4A). DMSO-treated HeLa cells normally progressed through mitosis with a mean time of 67.4 ± 32.4 min, followed by cytokinesis (87.1% bipolar division leading to two daughter cells, Fig. 4A). Furthermore, the cell fate of asymmetrically divided HeLa-H2B-GFP after TH treatment was analyzed by time-lapse microscopy. As depicted in Figure 4B, some first generation daughter cells derived from asymmetric divisions died in an interphase-like state without entering another round of division, whereas other daughter cells died ...
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... the cell fate of asymmetrically divided HeLa-H2B-GFP after TH treatment was analyzed by time-lapse microscopy. As depicted in Figure 4B, some first generation daughter cells derived from asymmetric divisions died in an interphase-like state without entering another round of division, whereas other daughter cells died during the next cell cycle round, or went through another round of asymmetric division, after which second generation offspring failed to divide further and died in an interphase-like state. ...
Citations
... The compounds also induce mitochondrial dysfunction, apoptosis as well as cytotoxicity and inhibit the activity of telomerase. Another compound obtained from Dioscoreae rhizome when treated with both HeLa as well as C33A cells are able to upregulate JNK, PERK, Bax, PARP, p38, ATF4, caspase-3, -8, -9 while it downregulates the level of Bcl-2 [93][94][95]. It also initiates induction of ROS and the ER stress pathway. ...
Cervical cancer is defined as a cancer arising in the cells of cervix that causes unusual vaginal bleeding, discharges, pain in the pelvic region, or pain during sexual activity. Cervical cancer is currently reported to be the fourth most prevalent malignancy among women globally. Surgery includes pelvic lymphadenectomy as well as radical hysterectomy, radiotherapy, as well as chemotherapy are the most common therapies for treating cervical cancer. Another approach includes targeted medication which affects the epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) for the curing cervical cancer. However, these therapies have the potential for risks and complications: surgery can result in bleeding and may cause organ damage surrounding the surgery, and clots may also start to form in the deep veins of the legs; radiotherapy can result in menopause, infertility, discomfort, or pain during intercourse; and chemotherapy can actually impact rapidly dividing cells along with cancer cells in the human body system. In this review, we will discuss about the use of several Randomised controlled trials (RCTs) for treating malnutrition in various oncology patients. In this review, we will discuss about the various therapeutic effects of natural products isolated from different microorganisms in treating cervical cancer.
... PC generally has 99% overall survival for ten years if detected and treated early 3 . However metastatic castrate-resistant PCa (mCRPC) form remains incurable 2,4 . ...
... Volasertib and Alisertib (MNL8237), inhibitors of vital regulators of mitosis, have shown hopeful clinical efficacy in a variety of malignancies, including PC and acute myeloid leukemia. To date, microtubule-targeting drugs are the most effective mitosis inhibitors in chemotherapy strategies 4 . Docetaxel and cabazitaxel are widely used to treat PC in a chemotherapeutic approach. ...
... 18 . The GSE83459 dataset was collected as a dataset comparing PC (LNCaP cell line)/TH and non-treatable PC (LNCaP cell line) 4 . Differentially-Expressed Genes (DEGs) were identified according to (p<0.05) and (log2 fold change >0.5 and <-0.5. ...
Background:
Uncontrolled mitosis of cancer cells and resistance cells to chemotherapy drugs are the challenges of prostate cancer. Thalicthuberine causes a mitotic arrest and a reduction of the effects of drug resistance, resulting in cell death. In this study, we applied bioinformatics and computational biology methods to identify functional pathways and side effects in response to Thalicthuberine in prostate cancer patients.
Methods:
Microarray data were retrieved from Gene Expression Omnibus (GEO), and protein-protein interactions and gene regulatory networks were constructed, using the Cytoscape software. The critical genes and molecular mechanisms in response to Thalicthuberine and its side effects were identified, using the Cytoscape software and WebGestalt server, respectively. Finally, GEPIA2 was used to predict the relationship between critical genes and prostate cancer.
Results:
The POLQ, EGR1, CDKN1A, FOS, MDM2, CDC20, CCNB1, and CCNB2 were identified as critical genes in response to this drug. The functional mechanisms of Thalicthuberine include a response to oxygen levels, toxic substances and immobilization stress, cell cycle regulation, regeneration, the p53 signaling pathway, the action of the parathyroid hormone, and the FoxO signaling pathway. Besides, the drug has side effects including muscle cramping, abdominal pains, paresthesia, and metabolic diseases.
Conclusion:
Our model suggested newly predicted crucial genes, molecular mechanisms, and possible side effects of this drug. However, further studies are required.
... PC generally has 99% overall survival for ten years if detected and treated early 3 . However metastatic castrate-resistant PCa (mCRPC) form remains incurable 2,4 . ...
... Volasertib and Alisertib (MNL8237), inhibitors of vital regulators of mitosis, have shown hopeful clinical efficacy in a variety of malignancies, including PC and acute myeloid leukemia. To date, microtubule-targeting drugs are the most effective mitosis inhibitors in chemotherapy strategies 4 . Docetaxel and cabazitaxel are widely used to treat PC in a chemotherapeutic approach. ...
... 18 . The GSE83459 dataset was collected as a dataset comparing PC (LNCaP cell line)/TH and non-treatable PC (LNCaP cell line) 4 . Differentially-Expressed Genes (DEGs) were identified according to (p<0.05) and (log2 fold change >0.5 and <-0.5. ...
Background: Uncontrolled mitosis of cancer cells and resistance cells to chemotherapy drugs are the challenges of prostate cancer. Thalicthuberine causes a mitotic arrest and a reduction of the effects of drug resistance, resulting in cell death. In this study, we applied bioinformatics and computational biology methods to identify functional pathways and side effects in response to Thalicthuberine in prostate cancer patients. Methods: Microarray data were retrieved from Gene Expression Omnibus (GEO), and protein-protein interactions and gene regulatory networks were constructed, using the Cytoscape software. The critical genes and molecular mechanisms in response to Thalicthuberine and its side effects were identified, using the Cytoscape software and WebGestalt server, respectively. Finally, GEPIA2 was used to predict the relationship between critical genes and prostate cancer. Results: The POLQ, EGR1, CDKN1A, FOS, MDM2, CDC20, CCNB1, and CCNB2 were identified as critical genes in response to this drug. The functional mechanisms of Thalicthuberine include a response to oxygen levels, toxic substances and immobiliza-tion stress, cell cycle regulation, regeneration, the p53 signaling pathway, the action of the parathyroid hormone, and the FoxO signaling pathway. Besides, the drug has side effects including muscle cramping, abdominal pains, paresthesia, and metabolic diseases. Conclusion: Our model suggested newly predicted crucial genes, molecular mechanisms , and possible side effects of this drug. However, further studies are required.
... Notably, several natural products seem to cause mitotic catastrophe. Bioactive compounds such as gallic acid, pseudolaric acid B, or thalicthuberine result in arrest at the G 2 /M phase of cancer cells by disturbing centrosomal clustering, microtubule formation, or chromosome segregation, which contributes to mitotic catastrophe (9,27,28). Chelidonine and glyfoline can effectively cause the phosphorylation of histone H3 (Ser 10 ), which is an indicator of mitotic catastrophe, and thereby induce apoptotic cell death (10,29). Similar to previous studies, we found that EEJS treatment clearly led to the enrichment of enlarged multinucleated cells, disturbances of the mitotic spindle, and increased phosphorylation of histone H3 (Ser 10 ) in human oral cancer cells. ...
Mitotic catastrophe, a cell death mechanism characterized by abnormal mitosis, has been regarded as a therapeutic approach for the development of anti‑cancer drug candidates. The aim of the present study was to investigate the potential effect of the ethanolic extract of Juniperus squamata (EEJS) on the occurrence of mitotic catastrophe in human oral cancer cell lines. The effect of EEJS on the occurrence of mitotic catastrophe was evaluated by measuring cytotoxicity, observing phase‑contrast or transmission electron microscope findings, evaluating the appearance of microtubule or chromosome abnormalities, and detecting the phosphorylation of histone H3 (Ser10). The apoptotic effect of EEJS was assessed by detecting cleaved PARP, analyzing the sub‑G1 population, Annexin V‑FITC/PI double staining, western blot analysis, and the transient transfection of myeloid cell leukemia‑1 (Mcl‑1) overexpression vectors. EEJS treatment was effective in inhibiting cell proliferation in human oral cancer cell lines. EEJS resulted in the enrichment of enlarged multinucleated cells, the disturbance of microtubule formation, and increased phosphorylation of histone H3 (Ser10), which demonstrates the occurrence of mitotic catastrophe. Additionally, the multinucleated cells underwent apoptotic cell death in a cell context‑dependent manner, which was associated with the reduction of Mcl‑1 protein levels. Findings of the present study indicate that EEJS could be effective for treating human oral cancer by promoting mitotic catastrophe linked to apoptotic cell death.
... The lower degree of tumor necrosis, less mitotic activity and better definition of tumor borders, sometimes showing areas of peritumoral fibrosis. The mitotic index provides evidence about tumor proliferative activity; the formation of areas of necrosis is often associated with cell proliferation so intense and rapid that neovascularization does not occur with the speed necessary to provide nutrition to tumor cells and, thus, suggesting high proliferative activity; lymphocytic peritumoral fibrosis provide evidence about the interaction between tumor and host tissues [54]. Thus, it is possible to speculate that such findings, almost not observed in the other groups, could be related to a less aggressive biological behavior of tumors treated with 5-FU and POH/β-CD (50 mg/kg). ...
The low solubility and high volatility of perillyl alcohol (POH) compromise its bioavailability and potential use as chemotherapeutic drug. In this work, we have evaluated the anticancer activity of POH complexed with β-cyclodextrin (β-CD) using three complexation approaches. Molecular docking suggests the hydrogen-bond between POH and β-cyclodextrin in molar proportion was 1:1. Thermal analysis and Fourier-transform infrared spectroscopy (FTIR) confirmed that the POH was enclosed in the β-CD cavity. Also, there was a significant reduction of particle size thereof, indicating a modification of the β-cyclodextrin crystals. The complexes were tested against human L929 fibroblasts after 24 h of incubation showing no signs of cytotoxicity. Concerning the histopathological results, the treatment with POH/β-CD at a dose of 50 mg/kg promoted approximately 60% inhibition of tumor growth in a sarcoma S180-induced mice model and the reduction of nuclear immunoexpression of the Ki67 antigen compared to the control group. Obtained data suggest a significant reduction of cycling cells and tumor proliferation. Our results confirm that complexation of POH/β-CD not only solves the problem related to the volatility of the monoterpene but also increases its efficiency as an antitumor agent.
... Finally, it induced apoptosis and cell cycle arrest in HeLa cells. Levrier et al. suggested that thalicthuberine from Hernandia albiflora downregulated tubulin polymers on HeLa cells [90]. They used HeLa cells expressing the end-binding protein (EB1-GFP) with thalicthuberine. ...
Cervical cancer is the fourth most common cancer among women worldwide. Though several natural products have been reported regarding their efficacies against cervical cancer, there has been no review article that categorized them according to their anti-cancer mechanisms. In this study, anti-cancerous natural products against cervical cancer were collected using Pubmed (including Medline) and google scholar, published within three years. Their mechanisms were categorized as induction of apoptosis, inhibition of angiogenesis, inhibition of metastasis, reduction of resistance, and regulation of miRNAs. A total of 64 natural products suppressed cervical cancer. Among them, Penicillium sclerotiorum extracts from Cassia fistula L., ethanol extracts from Bauhinia variegate candida, thymoquinone obtained from Nigella sativa, lipid-soluble extracts of Pinellia pedatisecta Schott., and 1′S-1′-acetoxychavicol extracted from Alpinia conchigera have been shown to have multi-effects against cervical cancer. In conclusion, natural products could be attractive candidates for novel anti-cancer drugs.
... Thalicthuberine was isolated from Hernandia albiflora Kubitzki, an Australian endemic tree. This compound was treated to LNCaP (2.5 µM), CEM (5 and 10 µM), and VCR-R (60 µM), and the results showed an increase in caspase3/7 activity [51]. Triterpenoid plectranthoic acid is a dietary compound derived from Ficus microcarpa Linne. ...
Prostate cancer is the third most common cancer worldwide, and the burden of the disease is increased. Although several chemotherapies have been used, concerns about the side effects have been raised, and development of alternative therapy is inevitable. The purpose of this study is to prove the efficacy of dietary substances as a source of anti-tumor drugs by identifying their carcinostatic activities in specific pathological mechanisms. According to numerous studies, dietary substances were effective through following five mechanisms; apoptosis, anti-angiogenesis, anti-metastasis, microRNA (miRNA) regulation, and anti-multi-drug-resistance (MDR). About seventy dietary substances showed the anti-prostate cancer activities. Most of the substances induced the apoptosis, especially acting on the mechanism of caspase and poly adenosine diphosphate ribose polymerase (PARP) cleavage. These findings support that dietary compounds have potential to be used as anticancer agents as both food supplements and direct clinical drugs.
... Thalicthuberine, a phenanthrene alkaloid isolated from Hernandia albiflora (Hernandiaceae), is known for its antimicrobial activity (74). Levrier et al. (75) examined its antimitotic activity in prostate (PC-3) and cervical cancer (HeLa) cells and established respective IC 50 of 0.7 and 2.5 mmol/L. This promising agent did not directly inhibit tubulin polymerisation, but it destroyed cellular tubulin polymers and suppressed mitotic spindle dynamics. ...
The entire world is looking for effective cancer therapies whose benefits would outweigh their toxicity. One way to reduce resistance to chemotherapy and its adverse effects is the so called targeted therapy, which targets specific molecules (“molecular targets”) that play a critical role in cancer growth, progression, and metastasis. One such specific target are microtubules. In this review we address the current knowledge about microtubule-targeting agents or drugs (MTAs/MTDs) used in cancer therapy from their synthesis to toxicities. Synthetic and natural MTAs exhibit antitumor activity, and preclinical and clinical studies have shown that their anticancer effectiveness is higher than that of traditional drug therapies. Furthermore, MTAs involve a lower risk of adverse effects such as neurotoxicity and haemotoxicity. Several new generation MTAs are currently being evaluated for clinical use. This review brings updated information on the benefits of MTAs, therapeutic approaches, advantages, and challenges in their research.
Cells have evolved intricate mechanisms for dividing their contents in the most symmetric way during mitosis. However, a small proportion of cell divisions results in asymmetric segregation of cellular components, which leads to differences in the characteristics of daughter cells. Although the classical function of asymmetric cell division (ACD) in the regulation of pluripotency is the generation of one differentiated daughter cell and one self-renewing stem cell, recent evidence suggests that ACD plays a role in other physiological processes. In cancer, tumor heterogeneity can result from the asymmetric segregation of genetic material and other cellular components, resulting in cell-to-cell differences in fitness and response to therapy. Defining the contribution of ACD in generating differences in key features relevant to cancer biology is crucial to advancing our understanding of the causes of tumor heterogeneity and developing strategies to mitigate or counteract it. In this Review, we delve into the occurrence of asymmetric mitosis in cancer cells and consider how ACD contributes to the variability of several phenotypes. By synthesizing the current literature, we explore the molecular mechanisms underlying ACD, the implications of phenotypic heterogeneity in cancer, and the complex interplay between these two phenomena.
Cytoskeleton plays a significant role in the shape change, migration, movement, adhesion, cytokinesis, and phagocytosis of tumor cells. In clinical practice, some anti-cancer drugs achieve cytoskeletal therapeutic effects by acting on different cytoskeletal protein components. However, in the absence of cell-specific targeting, unnecessary cytoskeletal recombination in organisms would be disastrous, which would also bring about severe side effects during anticancer process. Nanomedicine have been proven to be superior to some small molecule drugs in cancer treatment due to better stability and targeting, and lower side effects. Therefore, this review summarized the recent developments of various nanomaterials disturbing cytoskeleton for enhanced cancer therapeutics, including carbon, noble metals, metal oxides, black phosphorus, calcium, silicon, polymers, peptides, and metal-organic frameworks, etc. A comprehensive analysis of the characteristics of cytoskeleton therapy as well as the future prospects and challenges towards clinical application were also discussed. We aim to drive on this emerging topic through refreshing perspectives based on our own work and what we have also learnt from others. This review will help researchers quickly understand relevant cytoskeletal therapeutic information to further advance the development of cancer nanomedicine.
