Displaying publications 1 - 20 of 359 in total

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  1. Fulltext Can Natural Products Targeting EMT Serve as the Future Anticancer Therapeutics?
    Anwar S, Malik JA, Ahmed S, Kameshwar VA, Alanazi J, Alamri A, et al.
    Molecules, 2022 Nov 08;27(22).
    PMID: 36431766 DOI: 10.3390/molecules27227668
    Cancer is the leading cause of death and has remained a big challenge for the scientific community. Because of the growing concerns, new therapeutic regimens are highly demanded to decrease the global burden. Despite advancements in chemotherapy, drug resistance is still a major hurdle to successful treatment. The primary challenge should be identifying and developing appropriate therapeutics for cancer patients to improve their survival. Multiple pathways are dysregulated in cancers, including disturbance in cellular metabolism, cell cycle, apoptosis, or epigenetic alterations. Over the last two decades, natural products have been a major research interest due to their therapeutic potential in various ailments. Natural compounds seem to be an alternative option for cancer management. Natural substances derived from plants and marine sources have been shown to have anti-cancer activity in preclinical settings. They might be proved as a sword to kill cancerous cells. The present review attempted to consolidate the available information on natural compounds derived from plants and marine sources and their anti-cancer potential underlying EMT mechanisms.
    Matched MeSH terms: Cell Cycle
  2. Selective pks+ Escherichia coli strains induce cell cycle arrest and apoptosis in colon cancer cell line
    Zulpa AK, Barathan M, Iyadorai T, Mariappan V, Vadivelu J, Teh CSJ, et al.
    World J Microbiol Biotechnol, 2023 Oct 06;39(12):333.
    PMID: 37801157 DOI: 10.1007/s11274-023-03767-1
    pks+ Escherichia coli (E. coli) triggers genomic instability in normal colon cells which leads to colorectal cancer (CRC) tumorigenesis. Previously, we reported a significant presentation of pks+ E. coli strains in CRC patients' biopsies as compared to healthy cohorts. In this work, using an in vitro infection model, we further explored the ability of these strains in modulating cell cycle arrest and activation of apoptotic mediators in both primary colon epithelial cells (PCE) and CRC cells (HCT-116). Sixteen strains, of which eight tumours and the matching non-malignant tissues, respectively, from eight pks+ E. coli CRC patients were subjected to BrDU staining and cell cycle analysis via flow cytometry, while a subset of these strains underwent analysis of apoptotic mediators including caspase proteins, cellular reactive oxygen species (cROS) and mitochondrial membrane potential (MMP) via spectrophotometry as well as proinflammatory cytokines via flow cytometry. Data revealed that all strains exerted S-phase cell cycle blockade in both cells and G2/M phase in PCE cells only. Moreover, more significant upregulation of Caspase 9, cROS, proinflammatory cytokines and prominent downregulation of MMP were detected in HCT-116 cells indicating the potential role of pks related bacterial toxin as anticancer agent as compared to PCE cells which undergo cellular senescence leading to cell death without apparent upregulation of apoptotic mediators. These findings suggest the existence of discrepancies underlying the mechanism of action of pks+ E. coli on both cancer and normal cell lines. This work propounds the rationale to further understand the mechanism underlying pks+ E. coli-mediated CRC tumorigenesis and cancer killing.
    Matched MeSH terms: Cell Cycle; Cell Cycle Checkpoints
  3. Fulltext THE EFFECT OF Diopatra claparediiGrube, 1878 AQUEOUSEXTRACT ON CHANG LIVER AND HUMAN PRIMARY GLIOBLASTOMA (U-87) CELL LINES
    AMIRAH IDRIS, WAN IRYANI WAN ISMAIL, IZWANDY IDRIS, IZWANDY IDRIS
    UMT Journal of Undergraduate Research, 2019;1(3):56-67.
    MyJurnal
    The distinctive regenerative ability of local marine worm (polychaete),Diopatra claparediiGrube, 1878, has the potential as a cellular growth agent. In this study, the growth effect was investigatedin normal cellsand cancer cells. Different concentrations (0-100
    Matched MeSH terms: Cell Cycle
  4. Performance of Euler-Maruyama, 2-Stage SRK and 4-Stage SRK in Approximating the Strong Solution of Stochastic Model
    Norhayati Rosli, Arifah Bahar, Yeak SH, Haliza Abdul Rahman, Madihah Md. Salleh
    Sains Malaysiana, 2010;39.
    Stochastic differential equations play a prominent role in many application areas including finance, biology and epidemiology. By incorporating random elements to ordinary differential equation system, a system of stochastic differential equations (SDEs) arises. This leads to a more complex insight of the physical phenomena than their deterministic counterpart. However, most of the SDEs do not have an analytical solution where numerical method is the best way to resolve this problem. Recently, much work had been done in applying numerical methods for solving SDEs. A very general class of Stochastic Runge-Kutta, (SRK) had been studied and 2-stage SRK with order convergence of 1.0 and 4-stage SRK with order convergence of 1.5 were discussed. In this study, we compared the performance of Euler-Maruyama, 2-stage SRK and 4-stage SRK in approximating the strong solutions of stochastic logistic model which describe the cell growth of C. acetobutylicum P262. The MS-stability functions of these schemes were calculated and regions of MS-stability are given. We also perform the comparison for the performance of these methods based on their global errors.
    Matched MeSH terms: Cell Cycle
  5. Fulltext Investigation into the Molecular Mechanisms underlying the Anti-proliferative and Anti-tumorigenesis activities of Diosmetin against HCT-116 Human Colorectal Cancer
    Koosha S, Mohamed Z, Sinniah A, Alshawsh MA
    Sci Rep, 2019 03 26;9(1):5148.
    PMID: 30914796 DOI: 10.1038/s41598-019-41685-1
    Diosmetin (Dis) is a bioflavonoid with cytotoxicity properties against variety of cancer cells including hepatocarcinoma, breast and colorectal (CRC) cancer. The exact mechanism by which Dis acts against CRC however, still remains unclear, hence in this study, we investigated the possible molecular mechanisms of Dis in CRC cell line, HCT-116. Here, we monitored the viability of HCT-116 cells in the presence of Dis and investigated the underlying mechanism of Dis against HCT-116 cells at the gene and protein levels using NanoString and proteome profiler array technologies. Findings demonstrated that Dis exhibits greater cytotoxic effects towards HCT-116 CRC cells (IC50 = 3.58 ± 0.58 µg/ml) as compared to the normal colon CCD-841 cells (IC50 = 51.95 ± 0.11 µg/ml). Arrests of the cells in G2/M phase confirms the occurrence of mitotic disruption via Dis. Activation of apoptosis factors such as Fas and Bax at the gene and protein levels along with the release of Cytochrome C from mitochondria and cleavage of Caspase cascades indicate the presence of turbulence as a result of apoptosis induction in Dis-treated cells. Moreover, NF-ƙB translocation was inhibited in Dis-treated cells. Our results indicate that Dis can target HCT-116 cells through the mitotic disruption and apoptosis induction.
    Matched MeSH terms: G2 Phase Cell Cycle Checkpoints/drug effects*; M Phase Cell Cycle Checkpoints/drug effects*
  6. Circadian rhythms and cancer
    Selvaraj C, Safi SZ, Vijayakumar R
    Adv Protein Chem Struct Biol, 2023;137:135-159.
    PMID: 37709373 DOI: 10.1016/bs.apcsb.2023.05.001
    Circadian rhythms are autonomous oscillators developed by the molecular circadian clock, essential for coordinating internal time with the external environment in a 24-h daily cycle. In mammals, this circadian clock system plays a major role in all physiological processes and severely affects human health. The regulation of the circadian clock extends beyond the clock genes to involve several clock-controlled genes. Hence, the aberrant expression of these clock genes leads to the downregulation of important targets that control the cell cycle and the ability to undergo apoptosis. This may lead to genomic instability and promotes carcinogenesis. Alteration in the clock genes and their modulation is recognized as a new approach for the development of effective treatment against several diseases, including cancer. Until now, there has been a lack of understanding of circadian rhythms and cancer disease. For that, this chapter aims to represent the core components of circadian rhythms and their function in cancer pathogenesis and progression. In addition, the clinical impacts, current clock drugs, and potential therapeutic targets have been discussed.
    Matched MeSH terms: Cell Cycle
  7. Fulltext Anticancer properties and mechanism insights of α-hederin
    Belmehdi O, Taha D, Abrini J, Ming LC, Khalid A, Abdalla AN, et al.
    Biomed Pharmacother, 2023 Sep;165:115205.
    PMID: 37499451 DOI: 10.1016/j.biopha.2023.115205
    α-Hederin is a natural bioactive molecule very abundant in aromatic and medicinal plants (AMP). It was identified, characterized, and isolated using different extraction and characterization technologies, such as HPLC, LC-MS and NMR. Biological tests have revealed that this natural molecule possesses different biological properties, particularly anticancer activity. Indeed, this activity has been investigated against several cancers (e.g., esophageal, hepatic, breast, colon, colorectal, lung, ovarian, and gastric). The underlying mechanisms are varied and include induction of apoptosis and cell cycle arrest, reduction of ATP generation, as well as inhibition of autophagy, cell proliferation, invasion, and metastasis. In fact, these anticancer mechanisms are considered the most targeted for new chemotherapeutic agents' development. In the light of all these data, α-hederin could be a very interesting candidate as an anticancer drug for chemotherapy, as well as it could be used in combination with other molecules already validated or possibly investigated as an agent sensitizing tumor cells to chemotherapeutic treatments.
    Matched MeSH terms: Cell Cycle Checkpoints
  8. Fulltext Evaluation of selected tropical marine microalgal cultures for use in biophotovoltaic platforms
    Tay ZH, Ng FL, Thong CH, Lee CW, Gnana Kumar G, Al-Sehemi AG, et al.
    Appl Microbiol Biotechnol, 2024 Dec;108(1):1-14.
    PMID: 38194143 DOI: 10.1007/s00253-023-12951-0
    In this study, the bioelectrical power generation potential of four tropical marine microalgal strains native to Malaysia was investigated using BPV platforms. Chlorella UMACC 258 produced the highest power density (0.108 mW m-2), followed by Halamphora subtropica UMACC 370 (0.090 mW m-2), Synechococcus UMACC 371 (0.065 mW m-2) and Parachlorella UMACC 245 (0.017 mW m-2). The chlorophyll-a (chl-a) content was examined to have a linear positive relationship with the power density (p 
    Matched MeSH terms: Cell Cycle
  9. Fulltext Curcumin piperidone derivatives induce anti-proliferative and anti-migratory effects in LN-18 human glioblastoma cells
    Razali NSC, Lam KW, Rajab NF, A Jamal AR, Kamaluddin NF, Chan KM
    Sci Rep, 2022 Jul 30;12(1):13131.
    PMID: 35907913 DOI: 10.1038/s41598-022-16274-4
    Curcumin has demonstrated potential cytotoxicity across various cell lines despite its poor bioavailability and rapid metabolism. Therefore, our group have synthesized curcuminoid analogues with piperidone derivatives, FLDP-5 and FLDP-8 to overcome these limitations. In this study, the analogues were assessed on LN-18 human glioblastoma cells in comparison to curcumin. Results from cytotoxicity assessment showed that FLDP-5 and FLDP-8 curcuminoid analogues caused death in LN-18 cells in a concentration-dependent manner after 24-h treatment with much lower IC50 values of 2.5 µM and 4 µM respectively, which were more potent compared to curcumin with IC50 of 31 µM. Moreover, a significant increase (p cell death process induced by these analogues. These analogues also showed potent anti-migratory effects through inhibition of LN-18 cells' migration and invasion. In addition, cell cycle analysis showed that these analogues are capable of inducing significant (p cell cycle arrest during the 24-h treatment as compared to untreated, which explained the reduced proliferation indicated by MTT assay. In conclusion, these curcuminoid analogues exhibit potent anti-cancer effects with anti-proliferative and anti-migratory properties towards LN-18 cells as compared to curcumin.
    Matched MeSH terms: Cell Cycle Checkpoints
  10. Mechanisms of S-phase arrest and mitochondrial dysfunction in complex III by DHODH inhibitors in tumorigenic TNBC cells
    Shahhiran MAA, Abdul Kadir MF, Nor Rashid N, Abdul-Rahman PS, Othman S
    Histochem Cell Biol, 2024 Nov 18;163(1):3.
    PMID: 39557682 DOI: 10.1007/s00418-024-02339-0
    Dihydroorotate dehydrogenase (DHODH) inhibitors have recently gained increasing research interest owing to their potential for treating breast cancers. We explored their effects in different breast cancer subtypes, focusing on mitochondrial dysfunction. The sensitivity of different subtypes to the inhibitors was investigated with respect to DHODH expression, tumorigenic, and receptor status. Analysis of respiratory complexes, cell cycle, reactive oxygen species (ROS), and cell differentiation were performed. Four cell lines with different receptor status were included, namely MCF-7, MDAMB-231, SKBR-3, and MCF-10A. We showed that MCF-7 and MDAMB-231 cells of the subtypes (ER+/PR+/HER2-) and (ER-/PR-/HER2-), respectively, were responsive to brequinar. Brequinar (BQR) caused cell cycle arrest in the S-phase in sensitive subtypes of breast cells but induced cell differentiation only in poorly differentiated breast cells. All cell subtypes showed increased generation of ROS, both intracellular and mitochondrial ROS with a greater increase seen in mitochondrial ROS in response to DHODH inhibitor, subsequently contributing to mitochondrial dysfunction. BQR also disrupts the function of complex III in ER+/PR+ and triple negative breast cancer (TNBC) subtypes. Collectively, we have found that MDAMB-231 TNBC cell was the most affected by DHODH inhibition in terms of sensitivity, cell cycle arrest, induction of cell differentiation, production of ROS, and mitochondrial complexes disruption. In conclusion, these findings suggest that DHODH inhibitors can potentially become a valuable targeted therapy for TNBC subtype and further consolidates its therapeutic potential as part of the combinatorial therapy against this resilient breast cancer subtype.
    Matched MeSH terms: Cell Cycle Checkpoints/drug effects; S Phase Cell Cycle Checkpoints/drug effects
  11. Fulltext Dicranopteris linearis extract inhibits the proliferation of human breast cancer cell line (MDA-MB-231) via induction of S-phase arrest and apoptosis
    Baharuddin AA, Roosli RAJ, Zakaria ZA, Md Tohid SF
    Pharm Biol, 2018 Dec;56(1):422-432.
    PMID: 30301390 DOI: 10.1080/13880209.2018.1495748
    CONTEXT: Dicranopteris linearis (Burm.f.) Underw. (Gleicheniaceae) has been scientifically proven to exert various pharmacological activities. Nevertheless, its anti-proliferative potential has not been extensively investigated.

    OBJECTIVE: To investigate the anti-proliferative potential of D. linearis leaves and determine possible mechanistic pathways.

    MATERIALS AND METHODS: MTT assay was used to determine the cytotoxic effects of D. linearis methanol (MEDL) and petroleum ether (PEEDL) extracts at concentrations of 100, 50, 25, 12.5, 6.25 and 3.125 µg/mL against a panel of cancer cell lines (breast [MCF-7 and MDA-MB-231], cervical [HeLa], colon [HT-29], hepatocellular [HepG2] and lung [A549]), as compared to negative (untreated) and positive [5-fluorouracil (5-FU)-treated] control groups. Mouse fibroblast cells (3T3) were used as normal cells. The mode of cell death was examined using morphological analysis via acridine orange (AO) and propidium iodide (PI) double staining. Cell cycle arrest was determined using flow cytometer, followed by annexin V-PI apoptosis detection kit.

    RESULTS: MEDL demonstrated the most significant growth inhibition against MDA-MB-231 cells (IC50 22.4 µg/mL). PEEDL showed no cytotoxic effect. Induction of apoptosis by MEDL was evidenced via morphological analysis and acridine orange propidium iodide staining. MEDL could induce S phase cell cycle arrest after 72 h of incubation. Early apoptosis induction in MDA-MB-231 cells was confirmed by annexin V-FITC and PI staining. Significant increase in apoptotic cells were detected after 24 h of treatment with 15.07% cells underwent apoptosis, and the amount escalated to 18.24% with prolonged 48 h incubation.

    CONCLUSIONS: MEDL has potential as a potent cytotoxic agent against MDA-MB-231 adenocarcinoma.

    Matched MeSH terms: Cell Cycle Checkpoints/drug effects*; Cell Cycle Checkpoints/physiology; S Phase Cell Cycle Checkpoints/drug effects*; S Phase Cell Cycle Checkpoints/physiology
  12. Fulltext Mesenchymal stem cells inhibit proliferation of lymphoid origin haematopoietic tumour cells by inducing cell cycle arrest
    Sarmadi VH, Tong CK, Vidyadaran S, Abdullah M, Seow HF, Ramasamy R
    Med J Malaysia, 2010 Sep;65(3):209-14.
    PMID: 21939170
    We have previously shown that mesenchymal stem cells (MSC) inhibit tumour cell proliferation, thus promising a novel therapy for treating cancers. In this study, MSC were generated from human bone marrow samples and characterised based on standard immunophenotyping. When MSC were co-cultured with BV173 and Jurkat tumour cells, the proliferation of tumour cells were profoundly inhibited in a dose dependent manner mainly via cell to cell contact interaction. Further cell cycle analysis reveals that MSC arrest tumour cell proliferation in G0/G1 phase of cell cycle thus preventing the entry of tumour cells into S phase of cell cycle.
    Matched MeSH terms: Cell Cycle*
  13. Fulltext A rare X-linked inherited mucocutaneous syndrome in two siblings
    Chong LA, Ariffin H
    Med J Malaysia, 2009 Dec;64(4):327-9.
    PMID: 20954562 MyJurnal
    We report on an 11 year-old boy with dyskeratosis congenita who presented with dystrophic nails, dysphagia, hyperpigmentation and oral leukoplakia. He had a brother who died 14 years earlier with similar presenting symptoms and aplastic anaemia. Genetic studies of our patient demonstrated the presence of a DKC1 mutation and confirmed our diagnosis. Further genetic screening revealed that his mother and one of his four sisters are heterozygous for the same mutation.
    Matched MeSH terms: Cell Cycle Proteins/genetics
  14. X-linked dyskeratosis congenita in Malaysia
    Hamidah A, Rashid RA, Jamal R, Zhao M, Kanegane H
    Pediatr Blood Cancer, 2008 Feb;50(2):432.
    PMID: 17417794
    Matched MeSH terms: Cell Cycle Proteins/genetics*
  15. Epstein-Barr virus-encoded latent membrane protein-1 upregulates 14-3-3σ and Reprimo to confer G(2)/M phase cell cycle arrest
    Yeo KS, Mohidin TB, Ng CC
    C. R. Biol., 2012 Dec;335(12):713-21.
    PMID: 23312294 DOI: 10.1016/j.crvi.2012.11.002
    Epstein-Barr virus (EBV) is a ubiquitous tumor-causing virus which infects more than 90% of the world population asymptomatically. Recent studies suggest that LMP-1, -2A and -2B cooperate in the tumorigenesis of EBV-associated epithelial cancers such as nasopharygeal carcinoma, oral and gastric cancer. In this study, LMPs were expressed in the HEK293T cell line to reveal their oncogenic mechanism via investigation on their involvement in the regulation of the cell cycle and genes that are involved. LMPs were expressed in HEK293T in single and co-expression manner. The transcription of cell cycle arrest genes were examined via real-time PCR. Cell cycle progression was examined via flow cytometry. 14-3-3σ and Reprimo were upregulated in all LMP-1 expressing cells. Moreover, cell cycle arrest at G(2)/M progression was detected in all LMP-1 expressing cells. Therefore, we conclude that LMP-1 may induce cell cycle arrest at G(2)/M progression via upregulation of 14-3-3σ and Reprimo.
    Matched MeSH terms: Cell Cycle Proteins/genetics*; Cell Cycle Checkpoints/genetics*; G2 Phase Cell Cycle Checkpoints/genetics; M Phase Cell Cycle Checkpoints/genetics
  16. Fulltext Involvement of the uridine cytidine kinase 2 enzyme in cancer cell death: A molecular crosstalk between the enzyme and cellular apoptosis induction
    Malami I, Abdul AB
    Biomed Pharmacother, 2019 Jan;109:1506-1510.
    PMID: 30551402 DOI: 10.1016/j.biopha.2018.10.200
    Apoptosis is a series of molecular signalling regulating normal cellular growth and development. Cells resistance to apoptosis, however, leads to uncontrolled proliferation. Research involving cancer cell death is one of the most important targeted areas in the discovery of novel anticancer therapy. There are several biochemical pathways that are liked towards cancer cell death of which, uridine-cytidine kinase 2 (UCK2) was recently linked to cell apoptosis induction. UCK2 is responsible for the phosphorylation of uridine and cytidine to their corresponding monophosphate in a salvage pathway of pyrimidine nucleotides biosynthesis. Cytotoxic ribonucleoside analogues that target UCK2 enzyme activity are currently being investigated in clinical trials useful for cancer treatment. Whilst findings have clearly shown that these antimetabolites inhibit cancer development in clinical settings, they have yet to establish linking cytotoxic nucleoside analogues to cancer cell death. In this present review, we propose the probable molecular crosstalk involving UCK2 protein and cancer cell death through cell cycle arrest and triggering of apoptosis involving proteins, MDM2 and the subsequent activation of p53.
    Matched MeSH terms: Cell Cycle Checkpoints/physiology
  17. Fulltext Mesenchymal stem cells: a modern tool for immunomodulation
    Rajesh Ramasamy
    Malaysian Journal of Medicine and Health Sciences, 2019;15(108):13-13.
    MyJurnal
    Immunomodulation is essential for controlling the immune system to maintain efficient immune surveillance and inflammation. Both arms of immunomodulation, namely immunostimulation and immunosuppression, are equally crucial in setting the optimal balance of immune response. However, diseases or conditions such as autoimmune diseases, tissue rejection due to transplantation and chronic inflammation require downregulation of overwhelming immune reactions. The conventional immunosuppressive drugs prevent the activation of immune cells, yet create an unsafe condition with toxic adverse effects. In such predicament, mesenchymal stem cells (MSCs) emerged as one of the safe immunosuppressive regiments and widely tested in clinical trials for numerous chronic inflammatory dis-eases. Mesenchymal stem cells are the origin of the stromal/mesenchymal cells in almost all solid organs, including the pulp of the tooth. In addition to providing structural support to the organ, MSCs participate in the tissue repair and regeneration by ameliorating an overly activated immune response locally and systemically. Regardless of the source, MSCs profoundly suppress the proliferation and effector functions of both innate and adaptive immune cells. The mechanism of inhibition primarily took place in the early phase of cell cycle and mediated via suppression of mainstream signalling pathways that involve cyclins and other cell cycle proteins. The antiproliferative activity of MSCs is not only limited to the healthy immune cells but extends to the various tumour cells of the immune system. Similarly, an array of cell signalling pathways that executed by cell cycle proteins found downregulated in the pres-ence of MSCs. The immunosuppressive activity exerted by MSCs is not specific to particular immune cells where it impairs a group of the common cell signalling pathways or putative cell cycle proteins which are vital elements for the proliferation.
    Matched MeSH terms: Cell Cycle; Cell Cycle Proteins
  18. Fulltext Regulation of Plasmodium falciparum cell cycle involving cyclins and cyclin dependent kinases
    Siti Nurfatimah Mohd Shahpudin, Doblin Anak Sandai, Sharlina Mohamad
    Malaysian Journal of Medicine and Health Sciences, 2020;16(102):60-67.
    MyJurnal
    Protein kinases (PKs) are regulators of protein phosphorylation in many infectious diseases, including malaria. How- ever, the cellular functions of majority of PKs in Plasmodium falciparum remain unknown. The mechanisms involved in P. falciparum cell cycle progress are not fully understood. The activation of cyclin-dependent kinases (CDKs), which constitute a PK family that includes crucial regulators of cell cycle progression in eukaryotes, is strictly being coordinated by the interaction with specific cyclins at well-defined points within the cell cycle. These cyclin/CDK complexes are very well characterised in humans, but little is known in P. falciparum. This review expand our un- derstanding of the characteristic of CDKs and cyclins in P. falciparum, and paves the way for further investigations on the precise molecular role of these crucial regulatory proteins in mosquito and human. This represents a valuable step towards the elucidation of cell cycle control mechanisms in malaria parasites.
    Matched MeSH terms: Cell Cycle; Cell Cycle Checkpoints
  19. Dihydroorotate dehydrogenase (DHODH) inhibitors affect ATP depletion, endogenous ROS and mediate S-phase arrest in breast cancer cells
    Mohamad Fairus AK, Choudhary B, Hosahalli S, Kavitha N, Shatrah O
    Biochimie, 2017 Apr;135:154-163.
    PMID: 28196676 DOI: 10.1016/j.biochi.2017.02.003
    Dihydroorotate dehydrogenase (DHODH) is the key enzyme in de novo biosynthesis of pyrimidine in both prokaryotes and eukaryotes. The de novo pathway of pyrimidine biosynthesis is essential in cancer cells proliferation. Leflunomide is an approved DHODH inhibitor that has been widely used for the treatment of arthritis. Similarly, brequinar sodium is another DHODH inhibitor that showed anti-tumour effect in MC38 colon carcinoma cells when used in combination with fluorouracil. Despite the potential role of DHODH inhibitors in cancer therapy, their mechanisms of action remain obscure and await further elucidation. Here, we evaluated the effect of DHODH inhibitors on the production of ATP and ROS in sensitive and non-sensitive breast cancer cells. Subsequently, the effects of DHODH inhibitors on cell cycle as well as on signalling molecules such as p53, p65 and STAT6 were evaluated in sensitive T-47D and non-sensitive MDAMB-436 cells. The correlations between DHODH protein expression, proliferation speed and sensitivity to DHODH inhibitors were also investigated in a panel of cancer cell lines. DHODH inhibitors-sensitive T-47D and MDAMB-231 cells appeared to preserve ROS production closely to endogenous ROS level whereas the opposite was observed in non-sensitive MDAMB-436 and W3.006 cells. In addition, we observed approximately 90% of intracellular ATP depletion in highly sensitive T-47D and MDAMB-231 cells compared to non-sensitive MDAMB-436 cells. There was significant over-expression of p53, p65 and STAT6 signalling molecules in sensitive cells which may be involved in mediating the S-phase arrest in cell cycle progression. The current study suggests that DHODH inhibitors are most effective in cells that express high levels of DHODH enzyme. The inhibition of cell proliferation by these inhibitors appears to be accompanied by ROS production as well as ATP depletion. The increase in expression of signalling molecules observed may be due to pyrimidine depletion which subsequently leads to cell cycle arrest at S-phase.
    Matched MeSH terms: Cell Cycle; Cell Cycle Checkpoints
  20. Fulltext MicroRNAs Regulate Cell Cycle and Cell Death Pathways in Glioblastoma
    Sati ISEE, Parhar I
    Int J Mol Sci, 2021 Dec 17;22(24).
    PMID: 34948346 DOI: 10.3390/ijms222413550
    Glioblastoma (GBM), a grade IV brain tumor, is known for its heterogenicity and its resistance to the current treatment regimen. Over the last few decades, a significant amount of new molecular and genetic findings has been reported regarding factors contributing to GBM's development into a lethal phenotype and its overall poor prognosis. MicroRNA (miRNAs) are small non-coding sequences of RNA that regulate and influence the expression of multiple genes. Many research findings have highlighted the importance of miRNAs in facilitating and controlling normal biological functions, including cell differentiation, proliferation, and apoptosis. Furthermore, miRNAs' ability to initiate and promote cancer development, directly or indirectly, has been shown in many types of cancer. There is a clear association between alteration in miRNAs expression in GBM's ability to escape apoptosis, proliferation, and resistance to treatment. Further, miRNAs regulate the already altered pathways in GBM, including P53, RB, and PI3K-AKT pathways. Furthermore, miRNAs also contribute to autophagy at multiple stages. In this review, we summarize the functions of miRNAs in GBM pathways linked to dysregulation of cell cycle control, apoptosis and resistance to treatment, and the possible use of miRNAs in clinical settings as treatment and prediction biomarkers.
    Matched MeSH terms: Cell Cycle*
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