Displaying publications 261 - 280 of 1033 in total

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  1. Two new clerodane-type diterpenoids from Bornean liverwort Gottschelia schizopleura and their cytotoxic activity
    Ng SY, Kamada T, Suleiman M, Vairappan CS
    Nat Prod Res, 2018 Aug;32(15):1832-1837.
    PMID: 29156972 DOI: 10.1080/14786419.2017.1405409
    The Bornean liverwort Gottschelia schizopleura was investigated phytochemically for the first time. Two new and four previously known clerodane-type diterpenoids were isolated from the MeOH extract of G. schizopleura through a series of chromatographic techniques. The structures of the new metabolites were established by analyses of their spectroscopic data (1D NMR, 2D NMR, HRESIMS and IR). All the isolated compounds 1-6 were tested against human promyelocytic leukaemia (HL-60), human colon adenocarcinoma (HT-29) and Mus musculus skin melanoma (B16-F10). Compound 1 and 2 showed active inhibition against HL-60 and B16-F10 cells.
    Matched MeSH terms: Cell Line, Tumor
  2. A miRNA-145/TGF-β1 negative feedback loop regulates the cancer-associated fibroblast phenotype
    Melling GE, Flannery SE, Abidin SA, Clemmens H, Prajapati P, Hinsley EE, et al.
    Carcinogenesis, 2018 05 28;39(6):798-807.
    PMID: 29506142 DOI: 10.1093/carcin/bgy032
    The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-β1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-β1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-β signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-β1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.
    Matched MeSH terms: Cell Line, Tumor
  3. Characterization of keratin microparticles from feather biomass with potent antioxidant and anticancer activities
    Sharma S, Gupta A, Chik SMST, Kee CG, Mistry BM, Kim DH, et al.
    Int J Biol Macromol, 2017 Nov;104(Pt A):189-196.
    PMID: 28596005 DOI: 10.1016/j.ijbiomac.2017.06.015
    In the present study chicken feathers were hydrolyzed by chemical treatment in alkaline conditions. The pH value of feather hydrolyzed solution was amended accordingly the iso-electric precipitation. Two types of keratin microparticles KM1, KM2 were synthesized under acidic conditions at 3.5 and 5.5pH respectively. The synthesized keratin microparticles possessed uniform and round surface by scanning electron microscopy (SEM). The thermal degradation of microparticles were examined by thermogravimetry (TGA). Fourier transform infrared spectroscopy (FTIR) revealed that the extracted keratin retained the most of protein backbone. The microparticles were screened for their in vitro anticancer activities by SRB bioassay towards HeLa, SK-OV-3 and A549 cancer cell lines. Futhermore, their cytotoxicity towards healthy cell lines was analyzed having Malin Darby canine kidney (MDCK) cell lines along with in vitro antioxidant activity using DPPH and ABTS methods KM1 and KM2 showed 200.31±1.01 and 139.73±0.94, 214.16±0.29 and 153.92±0.61, 328.92±3.46 and 200.33±2.48μg/mL of IC50 levels against HeLa, SK-OV-3, and A549 cell lines, respectively. Moreover, KM1 and KM2 demonstrated significant antioxidant potency with IC50 levels 13.15 and 9.02μg/mL as well as 8.96 and 5.60μg/mL in DPPH and ABTS radical scavenging bioassay, respectively.
    Matched MeSH terms: Cell Line, Tumor
  4. Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway
    Break MKB, Hossan MS, Khoo Y, Qazzaz ME, Al-Hayali MZK, Chow SC, et al.
    Fitoterapia, 2018 Mar;125:161-173.
    PMID: 29355749 DOI: 10.1016/j.fitote.2018.01.006
    Cardamonin is a natural chalcone that has been shown to exhibit high anticancer activity. In an attempt to discover analogues of cardamonin with enhanced anticancer activity, 19 analogues were synthesized and tested against A549 and HK1 cell lines. Results of the MTS cell viability assay showed that several derivatives possessed cytotoxic activities that were several-fold more potent than cardamonin. SAR analysis showed the importance of the ketone and alkene groups for bioactivity, while substituting cardamonin's phenolic groups with more polar moieties resulted in activity enhancement. As part of the SAR study and further exploration of chemical space, the effect of metal coordination on cytotoxicity was also investigated, but it was only possible to successfully obtain the Cu (II) complex of cardamonin (19). Compound 19 was the most active analogue possessing IC50 values of 13.2μM and 0.7μM against A549 and HK1 cells, corresponding to a 5- and 32-fold increase in activity, respectively. It was also able to significantly inhibit the migration of A549 and HK1 cells. Further mode of action studies have shown that the most active analogue, 19, induced DNA damage resulting in G2/M-phase cell- cycle arrest in both cell lines. These events further led to the induction of apoptosis by the compound via caspase-3/7 and caspase-9 activation, PARP cleavage and downregulation of Mcl-1 expression. Moreover, 19 inhibited the expression levels of p-mTOR and p-4EBP1, which indicated that it exerted its anticancer activity, at least in part, via inhibition of the mTOR signalling pathway.
    Matched MeSH terms: Cell Line, Tumor
  5. 5-Fluorouracil ethosomes - skin deposition and melanoma permeation synergism with microwave
    Khan NR, Wong TW
    Artif Cells Nanomed Biotechnol, 2018;46(sup1):568-577.
    PMID: 29378453 DOI: 10.1080/21691401.2018.1431650
    This study focuses on the use of ethosome and microwave technologies to facilitate skin penetration and/or deposition of 5-fluorouracil in vitro and in vivo. Low ethanol ethosomes were designed and processed by mechanical dispersion technique and had their size, zeta potential, morphology, drug content and encapsulation efficiency characterized. The skin was pre-treated with microwave at 2450 MHz for 2.5 min with ethosomes applied topically and subjected to in vitro and in vivo skin drug permeation as well as retention evaluation. The drug and/or ethosomes cytotoxicity, uptake and intracellular trafficking by SKMEL-28 melanoma cell culture were evaluated. Pre-treatment of skin by microwave promoted significant drug deposition in skin from ethosomes in vitro while keeping the level of drug permeation unaffected. Similar observations were obtained in vivo with reduced drug permeation into blood. Combination ethosome and microwave technologies enhanced intracellular localization of ethosomes through fluidization of cell membrane lipidic components as well as facilitating endocytosis by means of clathrin, macropinocytosis and in particularly lipid rafts pathways. The synergistic use of microwave and ethosomes opens a new horizon for skin malignant melanoma treatment.
    Matched MeSH terms: Cell Line, Tumor
  6. In situ morphological assessment of apoptosis induced by Phaleria macrocarpa (Boerl.) fruit ethyl acetate fraction (PMEAF) in MDA-MB-231 cells by microscopy observation
    Kavitha N, Chen Y, Kanwar JR, Sasidharan S
    Biomed Pharmacother, 2017 Mar;87:609-620.
    PMID: 28081471 DOI: 10.1016/j.biopha.2016.12.127
    Phaleria macrocarpa (Boerl.) is a well-known medicinal plant and have been extensively used as traditional medicine for ages in treatment of various diseases. The purpose of this study was to determine the in situ cytotoxicity effect P. macrocarpa fruit ethyl acetate fraction (PMEAF) by using various conventional and modern microscopy techniques. The cytotoxicity of PMEAF treated MDA-MB-231 cells was determined through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay and CyQuant Cell Proliferation Assay after 24h of treatment. Both results were indicated that the PMEAF is a potential anticancer agent with the average IC50 values of 18.10μg/mL by inhibiting the MDA-MB-231 cell proliferation. Various conventional and modern microscopy techniques such as light microscopy, holographic microscopy, transmission (TEM) and scanning (SEM) electron microscope were used for the observation of morphological changes in PMEAF treated MDA-MB-231cells for 24h. The characteristic of apoptotic cell death includes cell shrinkage, membrane blebs, chromatin condensation and the formation of apoptotic bodies were observed. PMEAF might be the best candidate for developing more potent anticancer drugs or chemo-preventive supplements.
    Matched MeSH terms: Cell Line, Tumor
  7. Fulltext Blockade of c-Met-Mediated Signaling Pathways by E7050 Suppresses Growth and Promotes Apoptosis in Multidrug-Resistant Human Uterine Sarcoma Cells
    Huang TT, Chen CM, Lan YW, Lin SS, Choo KB, Chong KY
    Int J Mol Sci, 2022 Nov 28;23(23).
    PMID: 36499211 DOI: 10.3390/ijms232314884
    E7050 is a potent inhibitor of c-Met receptor tyrosine kinase and has potential for cancer therapy. However, the underlying molecular mechanism involved in the anti-cancer property of E7050 has not been fully elucidated. The main objective of this study was to investigate the anti-tumor activity of E7050 in multidrug-resistant human uterine sarcoma MES-SA/Dx5 cells in vitro and in vivo, and to define its mechanisms. Our results revealed that E7050 reduced cell viability of MES-SA/Dx5 cells, which was associated with the induction of apoptosis and S phase cell cycle arrest. Additionally, E7050 treatment significantly upregulated the expression of Bax, cleaved PARP, cleaved caspase-3, p21, p53 and cyclin D1, while it downregulated the expression of survivin and cyclin A. On the other hand, the mechanistic study demonstrated that E7050 inhibited the phosphorylation of c-Met, Src, Akt and p38 in HGF-stimulated MES-SA/Dx5 cells. Further in vivo experiments showed that treatment of athymic nude mice carrying MES-SA/Dx5 xenograft tumors with E7050 remarkably suppressed tumor growth. E7050 treatment also decreased the expression of Ki-67 and p-Met, and increased the expression of cleaved caspase-3 in MES-SA/Dx5 tumor sections. Therefore, E7050 is a promising drug that can be developed for the treatment of multidrug-resistant uterine sarcoma.
    Matched MeSH terms: Cell Line, Tumor
  8. Hypoxia-regulated microRNAs: the molecular drivers of tumor progression
    Sawai S, Wong PF, Ramasamy TS
    Crit Rev Biochem Mol Biol, 2022 Aug;57(4):351-376.
    PMID: 35900938 DOI: 10.1080/10409238.2022.2088684
    Hypoxia is a common feature of the tumor microenvironment (TME) of nearly all solid tumors, leading to therapeutic failure. The changes in stiffness of the extracellular matrix (ECM), pH gradients, and chemical balance that contribute to multiple cancer hallmarks are closely regulated by intratumoral oxygen tension via its primary mediators, hypoxia-inducible factors (HIFs). HIFs, especially HIF-1α, influence these changes in the TME by regulating vital cancer-associated signaling pathways and cellular processes including MAPK/ERK, NF-κB, STAT3, PI3K/Akt, Wnt, p53, and glycolysis. Interestingly, research has revealed the involvement of epigenetic regulation by hypoxia-regulated microRNAs (HRMs) of downstream target genes involved in these signaling. Through literature search and analysis, we identified 48 HRMs that have a functional role in the regulation of 5 key cellular processes: proliferation, metabolism, survival, invasion and migration, and immunoregulation in various cancers in hypoxic condition. Among these HRMs, 17 were identified to be directly associated with HIFs which include miR-135b, miR-145, miR-155, miR-181a, miR-182, miR-210, miR-224, miR-301a, and miR-675-5p as oncomiRNAs, and miR-100-5p, miR-138, miR-138-5p, miR-153, miR-22, miR-338-3p, miR-519d-3p, and miR-548an as tumor suppressor miRNAs. These HRMs serve as a potential lead in the development of miRNA-based targeted therapy for advanced solid tumors. Future development of combined HIF-targeted and miRNA-targeted therapy is possible, which requires comprehensive profiling of HIFs-HRMs regulatory network, and improved formula of the delivery vehicles to enhance the therapeutic kinetics of the targeted cancer therapy (TCT) moving forward.
    Matched MeSH terms: Cell Line, Tumor
  9. A RUNX1/ETO-SKP2-CDKN1B axis regulates expression of telomerase in t (8;21) acute myeloid leukemia
    Moses EJ, Azlan A, Khor KZ, Mot YY, Mohamed S, Seeni A, et al.
    Cell Mol Life Sci, 2023 Feb 23;80(3):70.
    PMID: 36820913 DOI: 10.1007/s00018-023-04713-y
    The fusion oncoprotein RUNX1/ETO which results from the chromosomal translocation t (8;21) in acute myeloid leukemia (AML) is an essential driver of leukemic maintenance. We have previously shown that RUNX1/ETO knockdown impairs expression of the protein component of telomerase, TERT. However, the underlying molecular mechanism of how RUNX1/ETO controls TERT expression has not been fully elucidated. Here we show that RUNX1/ETO binds to an intergenic region 18 kb upstream of the TERT transcriptional start site and to a site located in intron 6 of TERT. Loss of RUNX1/ETO binding precedes inhibition of TERT expression. Repression of TERT expression is also dependent on the destabilization of the E3 ubiquitin ligase SKP2 and the resultant accumulation of the cell cycle inhibitor CDKN1B, that are both associated with RUNX1/ETO knockdown. Increased CDKN1B protein levels ultimately diminished TERT transcription with E2F1/Rb involvement. Collectively, our results show that RUNX1/ETO controls TERT expression directly by binding to its locus and indirectly via a SKP2-CDKN1B-E2F1/Rb axis.
    Matched MeSH terms: Cell Line, Tumor
  10. Fulltext Knockdown of Stromal Interaction Molecule 1 (STIM1) Suppresses Acute Myeloblastic Leukemia-M5 Cell Line Survival Through Inhibition of Reactive Oxygen Species Activities
    Algariri ES, Mydin RBSMN, Moses EJ, Okekpa SI, Rahim NAA, Yusoff NM
    Turk J Haematol, 2023 Feb 28;40(1):11-17.
    PMID: 36404683 DOI: 10.4274/tjh.galenos.2022.2022.0246
    OBJECTIVE: This study aimed to investigate the role of the stromal interaction molecule 1 (STIM1) gene in the survival of the acute myeloblastic leukemia (AML)-M5 cell line (THP-1).

    MATERIALS AND METHODS: The STIM1 effect was assessed via dicersubstrate siRNA-mediated STIM1 knockdown. The effect of STIM1 knockdown on the expression of AKT and MAPK pathway-related genes and reactive oxygen species (ROS) generation-related genes was tested using real-time polymerase chain reaction. Cellular functions, including ROS generation, cell proliferation, and colony formation, were also evaluated following STIM1 knockdown.

    RESULTS: The findings revealed that STIM1 knockdown reduced intracellular ROS levels via downregulation of NOX2 and PKC. These findings were associated with the downregulation of AKT, KRAS, MAPK, and CMYC. BCL2 was also downregulated, while BAX was upregulated following STIM1 knockdown. Furthermore, STIM1 knockdown reduced THP-1 cell proliferation and colony formation.

    CONCLUSION: This study has demonstrated the role of STIM1 in promoting AML cell proliferation and survival through enhanced ROS generation and regulation of AKT/MAPK-related pathways. These findings may help establish STIM1 as a potential therapeutic target for AML treatment.

    Matched MeSH terms: Cell Line, Tumor
  11. Trailing TRAIL Resistance in Human Breast Adenocarcinoma Cells with Trichostatin A and Zebularine
    Wong SHM, Fang CM, Loh HS, Ngai SC
    Anticancer Agents Med Chem, 2023;23(7):817-831.
    PMID: 36380402 DOI: 10.2174/1871520623666221114095733
    AIMS: The aim of this study was to sensitize the resistant breast adenocarcinoma cells towards Tumour Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced apoptosis.

    BACKGROUND: Breast cancer is a heterogeneous disease involving complex mechanisms. TRAIL is a potential anticancer candidate for targeted treatment due to its selective killing effects on neoplastic cells. Nonetheless, resistance occurs in many cancers either intrinsically or after multiple treatments.

    OBJECTIVE: Therefore, this research investigated whether the combination of Trichostatin A (TSA) and Zebularine (Zeb) (TZ) followed by TRAIL (TZT) could sensitize the human breast adenocarcinoma cells towards apoptosis.

    METHODS: The breast adenocarcinoma cells, MDA-MB-231, MCF-7 and E-MDA-MB-231 (E-cadherin re-expressed MDA-MB-231) were treated with TSA, Zeb, TZ, TRAIL and TZT. The cells were subjected to hematoxylin and eosin (H & E) staining and FITC-Annexin V/Propidium Iodide apoptosis detection prior to proteome profiling.

    RESULTS: Based on morphological observation, apoptosis was induced in all cells treated with all treatment regimens though it was more evident for the TZT-treated cells. In the apoptosis detection analysis, TZ increased early apoptosis significantly in MDA-MB-231 and MCF-7 while TRAIL induced late apoptosis significantly in E-MDA-MB-231. Based on the proteome profiling on MDA-MB-231, TRAIL R2 and Fas expression was increased. For E-MDA-MB- 231, down-regulation of catalase, paraoxonase-2 (PON2), clusterin, an inhibitor of apoptosis proteins (IAPs) and cell stress proteins validated the notion that E-cadherin re-expression enhances TZT anti-cancer efficacy. Similar trend was observed in MCF-7 whereby TZT treatment down-regulated the anti-apoptotic catalase and PON2, increased the proapoptotic, B cell lymphoma 2 (Bcl-2)-associated agonist of cell death (Bad) and Bcl-2-associated X (Bax), second mitochondria-derived activator of caspase (SMAC) and HtrA serine peptidase 2 (HTRA2) as well as TRAIL receptors (TRAIL R1 and TRAIL R2).

    CONCLUSION: TZ treatment serves as an efficient treatment regimen for MDA-MB-231 and MCF-7, while TRAIL serves as a better treatment option for E-MDA-MB-231. Therefore, future studies on E-cadherin's positive regulatory role in TRAIL-induced apoptosis are warranted.

    Matched MeSH terms: Cell Line, Tumor
  12. Fulltext Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
    Yusoh NA, Chia SL, Saad N, Ahmad H, Gill MR
    Sci Rep, 2023 Jan 26;13(1):1456.
    PMID: 36702871 DOI: 10.1038/s41598-023-28454-x
    Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), "Ru-PIP", with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. Moreover, the identified combination was successfully able to inhibit the growth of A549 lung cancer spheroids and acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP.
    Matched MeSH terms: Cell Line, Tumor
  13. Fulltext Knockdown of Annexin A1 induces apoptosis, causing G2/M arrest and facilitating phagocytosis activity in human leukemia cell lines
    Hasan M, Kumolosasi E, Jantan I, Jasamai M, Nazarudin N
    Acta Pharm, 2022 Mar 01;72(1):109-122.
    PMID: 36651527 DOI: 10.2478/acph-2022-0005
    Annexin A1 (ANXA1) is an endogenous protein involved in the control of proliferation, cell cycle, phagocytosis, and apoptosis in several types of cancer. To investigate the effects of ANXA1 knockdown in leukemia cells, transfection with specific ANXA1 siRNA was performed. Cell cycle and apoptosis were analyzed using flow cytometry and a mechanism involving caspases and Bcl-2 was quantified using Western blotting. Phagocytosis activity was evaluated using hematoxylin & eosin staining. The ANXA1 expression was significantly downregulated after the knockdown and apoptosis was induced in tested cells. The expression of caspase-9 and -3 increased in U937 and Jurkat cells respectively. Bcl-2 expression was downregulated in K562 and Jurkat cells while upregulated in U937. The number of leukemic cells arrested at the G2/M phase and the phagocytosis index were significantly increased in transfected cells. This suggests that ANXA1 knockdown might be a potential approach in the therapeutic strategy for leukemia.
    Matched MeSH terms: Cell Line, Tumor
  14. Retarding breast tumor growth with nanoparticle-facilitated intravenous delivery of BRCA1 and BRCA2 tumor suppressor genes
    Ibnat N, Chowdhury EH
    Sci Rep, 2023 Jan 11;13(1):536.
    PMID: 36631481 DOI: 10.1038/s41598-022-25511-9
    Gene augmentation therapy entails replacement of the abnormal tumor suppressor genes in cancer cells. In this study, we performed gene augmentation for BRCA1/2 tumor suppressors in order to retard tumor development in breast cancer mouse model. We formulated inorganic carbonate apatite (CA) nanoparticles (NPs) to carry and deliver the purified BRCA1/2 gene- bearing plasmid DNA both in vitro and in vivo. The outcome of BRCA1/2 plasmid-loaded NPs delivery on cellular viability of three breast cancer cell lines such as MCF-7, MDA-MB-231 and 4T1 were evaluated by MTT assay. The result in MCF-7 cell line exhibited that transfection of BRCA 1/2 plasmids with CA NPs significantly reduced cancer cell growth in comparison to control group. Moreover, we noticed a likely pattern of cellular cytotoxicity in 4T1 murine cancer cell line. Following transfection with BRCA1 plasmid-loaded NPs, and Western blot analysis, a notable reduction in the phospho-MAPK protein of MAPK signaling pathway was detected, revealing reduced growth signal. Furthermore, in vivo study in 4T1 induced breast cancer mouse model showed that the tumor growth rate and final volume were decreased significantly in the mouse group treated intravenously with BRCA1 + NPs and BRCA2 + NPs formulations. Our results established that BRCA1/2 plasmids incorporated into CA NPs mitigated breast tumor growth, signifying their application in the therapy for breast cancer.
    Matched MeSH terms: Cell Line, Tumor
  15. Fulltext Proteomic time course of breast cancer cells highlights enhanced sensitivity to Stat3 and Src inhibitors prior to endocrine resistance development
    Madden SF, Cremona M, Farrelly AM, Low WH, McBryan J
    Cancer Gene Ther, 2023 Feb;30(2):324-334.
    PMID: 36266450 DOI: 10.1038/s41417-022-00548-0
    To prevent the development of endocrine-resistant breast cancer, additional targeted therapies are increasingly being trialled in combination with endocrine therapy. The molecular mechanisms facilitating cancer cell survival during endocrine treatment remain unknown but could help direct selection of additional targeted therapies. We present a novel proteomic timecourse dataset, profiling potential drug targets in a population of MCF7 cells during 1 year of tamoxifen treatment. Reverse phase protein arrays profiled >70 proteins across 30 timepoints. A biphasic response to tamoxifen was evident, which coincided with changes in growth rate. Tamoxifen strongly impeded cell growth for the first 160 days, followed by gradual growth recovery and eventual resistance development. The growth-impeded phase was distinguished by the phosphorylation of Stat3 (y705) and Src (y527). Tumour tissue from patients treated with neo-adjuvant endocrine therapy (<4 months) also displayed increased Stat3 and Src signalling. Inhibitors of Stat3 (napabucasin) and Src (dasatinib), were effective at killing tamoxifen-treated MCF7 and T47D cells. Sensitivity to both drugs was significantly enhanced once tamoxifen had induced the growth-impeded phase. This novel proteomic resource identifies key mechanisms enabling cell survival during tamoxifen treatment. It provides valuable insight into potential drug combinations and timing that may prevent the development of endocrine resistance.
    Matched MeSH terms: Cell Line, Tumor
  16. Fulltext In vitro antioxidant and antiproliferative activities of methanolic plant part extracts of Theobroma cacao
    Baharum Z, Akim AM, Taufiq-Yap YH, Hamid RA, Kasran R
    Molecules, 2014 Nov 10;19(11):18317-31.
    PMID: 25389662 DOI: 10.3390/molecules191118317
    The aims of this study were to determine the antioxidant and antiproliferative activity of the following Theobroma cacao plant part methanolic extracts: leaf, bark, husk, fermented and unfermented shell, pith, root, and cherelle. Antioxidant activity was determined using 2,2-diphenyl-2-picrylhydrazyl (DPPH), thiobarbituric acid-reactive substances (TBARS), and Folin-Ciocalteu assays; the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) assay was used to determine antiproliferative activity. The root extract had the highest antioxidant activity; its median effective dose (EC50) was 358.3±7.0 µg/mL and total phenolic content was 22.0±1.1 g GAE/100 g extract as compared to the other methanolic plant part extracts. Only the cherelle extract demonstrated 10.4%±1.1% inhibition activity in the lipid peroxidation assay. The MTT assay revealed that the leaf extract had the highest antiproliferative activity against MCF-7 cells [median inhibitory concentration (IC50)=41.4±3.3 µg/mL]. Given the overall high IC50 for the normal liver cell line WRL-68, this study indicates that T. cacao methanolic extracts have a cytotoxic effect in cancer cells, but not in normal cells. Planned future investigations will involve the purification, identification, determination of the mechanisms of action, and molecular assay of T. cacao plant extracts.
    Matched MeSH terms: Cell Line, Tumor
  17. Fulltext Potential lethal damage repair in glioblastoma cells irradiated with ion beams of various types and levels of linear energy transfer
    Chew MT, Nisbet A, Suzuki M, Matsufuji N, Murakami T, Jones B, et al.
    J Radiat Res, 2019 Jan 01;60(1):59-68.
    PMID: 30452663 DOI: 10.1093/jrr/rry081
    Glioblastoma (GBM), a Grade IV brain tumour, is a well-known radioresistant cancer. To investigate one of the causes of radioresistance, we studied the capacity for potential lethal damage repair (PLDR) of three altered strains of GBM: T98G, U87 and LN18, irradiated with various ions and various levels of linear energy transfer (LET). The GBM cells were exposed to 12C and 28Si ion beams with LETs of 55, 100 and 200 keV/μm, and with X-ray beams of 1.7 keV/μm. Mono-energetic 12C ions and 28Si ions were generated by the Heavy Ion Medical Accelerator at the National Institute of Radiological Science, Chiba, Japan. Clonogenic assays were used to determine cell inactivation. The ability of the cells to repair potential lethal damage was demonstrated by allowing one identical set of irradiated cells to repair for 24 h before subplating. The results show there is definite PLDR with X-rays, some evidence of PLDR at 55 keV/μm, and minimal PLDR at 100 keV/μm. There is no observable PLDR at 200 keV/μm. This is the first study, to the authors' knowledge, demonstrating the capability of GBM cells to repair potential lethal damage following charged ion irradiations. It is concluded that a GBM's PLDR is dependent on LET, dose and GBM strain; and the more radioresistant the cell strain, the greater the PLDR.
    Matched MeSH terms: Cell Line, Tumor
  18. New emerging targets in osteosarcoma therapy: PTEN and PI3K/Akt crosstalk in carcinogenesis
    Sadrkhanloo M, Paskeh MDA, Hashemi M, Raesi R, Bahonar A, Nakhaee Z, et al.
    Pathol Res Pract, 2023 Nov;251:154902.
    PMID: 37922723 DOI: 10.1016/j.prp.2023.154902
    Osteosarcoma (OS) is a malignant bone carcinoma that affects people in childhood and adulthood. The heterogeneous nature and chromosomal instability represent certain characteristics of OS cells. These cancer cells grow and migrate abnormally, making the prognosis undesirable for patients. Conventional and current treatments fail to completely eradicate tumor cells, so new therapeutics targeting genes may be considered. PI3K/Akt is a regulator of events such as growth, cell death, migration, and differentiation, and its expression changes during cancer progression. PTEN reduces PI3K/Akt expression, and its mutations and depletions have been reported in various tumors. Experimental evidence shows that there is upregulation of PI3K/Akt and downregulation of PTEN in OS. Increasing PTEN expression may suppress PI3K/Akt to minimize tumorigenesis. In addition, PI3K/Akt shows a positive association with growth, metastasis, EMT and metabolism of OS cells and inhibits apoptosis. Importantly, overexpression of PI3K/Akt causes drug resistance and radio-resistance and its level can be modulated by miRNAs, lncRNAs and circRNAs. Silencing PI3K/Akt by compounds and drugs can suppress OS. Here, we review in detail the function of the PTEN/PI3K/Akt in OS, revealing its biological function, function in tumor progression, resistance to therapy, and pharmacological significance.
    Matched MeSH terms: Cell Line, Tumor
  19. Cancer Cell-Derived PDGFB Stimulates mTORC1 Activation in Renal Carcinoma
    Abuhamad AY, Mohamad Zamberi NN, Vanharanta S, Mohd Yusuf SNH, Mohtar MA, Syafruddin SE
    Int J Mol Sci, 2023 Mar 29;24(7).
    PMID: 37047421 DOI: 10.3390/ijms24076447
    Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor that is characterized by bi-allelic inactivation of the VHL tumor suppressor gene and mTOR signalling pathway hyperactivation. The pro-angiogenic factor PDGFB, a transcriptional target of super enhancer-driven KLF6, can activate the mTORC1 signalling pathway in ccRCC. However, the detailed mechanisms of PDGFB-mediated mTORC1 activation in ccRCC have remained elusive. Here, we investigated whether ccRCC cells are able to secrete PDGFB into the extracellular milieu and stimulate mTORC1 signalling activity. We found that ccRCC cells secreted PDGFB extracellularly, and by utilizing KLF6- and PDGFB-engineered ccRCC cells, we showed that the level of PDGFB secretion was positively correlated with the expression of intracellular KLF6 and PDGFB. Moreover, the reintroduction of either KLF6 or PDGFB was able to sustain mTORC1 signalling activity in KLF6-targeted ccRCC cells. We further demonstrated that conditioned media of PDGFB-overexpressing ccRCC cells was able to re-activate mTORC1 activity in KLF6-targeted cells. In conclusion, cancer cell-derived PDGFB can mediate mTORC1 signalling pathway activation in ccRCC, further consolidating the link between the KLF6-PDGFB axis and the mTORC1 signalling pathway activity in ccRCC.
    Matched MeSH terms: Cell Line, Tumor
  20. Fulltext Mutated HRAS Activates YAP1-AXL Signaling to Drive Metastasis of Head and Neck Cancer
    Jagadeeshan S, Prasad M, Badarni M, Ben-Lulu T, Liju VB, Mathukkada S, et al.
    Cancer Res, 2023 Apr 04;83(7):1031-1047.
    PMID: 36753744 DOI: 10.1158/0008-5472.CAN-22-2586
    The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.

    SIGNIFICANCE: Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1-AXL axis and to stimulate lymphovascular angiogenesis.

    Matched MeSH terms: Cell Line, Tumor
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