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.
Various physiological processes involve appropriate tissue developmental process and homeostasis - the pathogenesis of several diseases connected with deregulatory apoptosis process. Apoptosis plays a crucial role in maintaining a balance between cell death and division, evasion of apoptosis results in the uncontrolled multiplication of cells leading to different diseases such as cancer. Currently, the development of apoptosis targeting anticancer drugs has gained much interest since cell death induced by apoptosis causes minimal inflammation. The understanding of complexities of apoptosis mechanism and how apoptosis is evolved by tumor cells to oppose cell death has focused research into the new strategies designed to induce apoptosis in cancer cells. This review focused on the underlying mechanism of apoptosis and the dysregulation of apoptosis modulators involved in the extrinsic and intrinsic apoptotic pathway, which include death receptors (DRs) proteins, cellular FLICE inhibitory proteins (c-FLIP), anti-apoptotic Bcl-2 proteins, inhibitors of apoptosis proteins (IAPs), tumor suppressor (p53) in cancer cells along with various current clinical approaches aimed to selectively induce apoptosis in cancer cells.
Matched MeSH terms: Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein
Honey is reported to contain various compounds such as phenols, vitamins and antioxidants. The present study investigates the anticancer potential of Tualang honey (Agromas) (TH) in human breast (MCF-7 and MDA-MB-231) and cervical (HeLa) cancer cell lines; as well as in the normal breast epithelial cell line, MCF-10A. The cells were treated with increasing doses of TH (1-10%) for up to 72 h. Increase in lactate dehydrogenase (LDH) leakage from the cell membranes indicates that TH is cytotoxic to all three cancer cells with effective concentrations (EC(50)) of 2.4-2.8%. TH is however, not cytotoxic to the MCF-10A cells. Reactivity with annexin V fluorescence antibody and propidium iodide as analysed by flow cytometry and fluorescence microscopy shows that apoptosis occurred in these cancer cells. TH also reduced the mitochondrial membrane potential (Δψ(m)) in the cancer cell lines after 24h of treatment. The activation of caspase-3/7 and -9 was observed in all TH-treated cancer cells indicating the involvement of mitochondrial apoptotic pathway. This study shows that TH has significant anticancer activity against human breast and cervical cancer cell lines.
Our previous work has shown that Saffold virus (SAFV) induced several rodent and primate cell lines to undergo apoptosis (Xu et al. in Emerg Microb Infect 3:1-8, 2014), but the essential viral proteins of SAFV involved in apoptotic activity lack study. In this study, we individually transfected the viral proteins of SAFV into HEp-2 and Vero cells to assess their ability to induce apoptosis, and found that the 2B and 3C proteins are proapoptotic. Further investigation indicated the transmembrane domain of the 2B protein is essential for the apoptotic activity and tetramer formation of the 2B protein. Our research provides clues for the possible mechanisms of apoptosis induced by SAFV in different cell lines. It also opens up new directions to study viral proteins (the 2B, 3C protein), and sets the stage for future exploration of any possible link between SAFV, inclusive of its related uncultivable genotypes, and multiple sclerosis.
Measuring at ~30 nm, a fully customizable holliday junction DNA nanoconstruct, was designed to simultaneously carry three unmodified SiRNA strands for apoptosis gene knockout in cancer cells without any assistance from commercial transfection kits. In brief, a holliday junction structure was intelligently designed to present one arm with a cell targeting aptamer (AS1411) while the remaining three arms to carry different SiRNA strands by means of DNA/RNA duplex for inducing apoptosis in cancer cells. By carrying the three SiRNA strands (AKT, MDM2 and Survivin) into triple negative breast MDA-MB-231 cancer cells, cell number had reduced by up to ~82% within 24 hours solely from one single administration of 32 picomoles. In the immunoblotting studies, up-elevation of phosphorylated p53 was observed for more than 8 hours while the three genes of interest were suppressed by nearly half by the 4-hour mark upon administration. Furthermore, we were able to demonstrate high cell selectivity of the nanoconstruct and did not exhibit usual morphological stress induced from liposomal-based transfection agents. To the best of the authors' knowledge, this system represents the first of its kind in current literature utilizing a short and highly customizable holliday DNA junction to carry SiRNA for apoptosis studies.
Although primary localised tumours of renal cell carcinoma (RCC) can be treated relatively successfully with surgery, metastatic RCC has poor prognosis because of late diagnosis and resistance to therapies. In the present study, we were interested in profiling the protein expression of "inhibitor of caspase-activated DNase" (ICAD), an apoptosis inhibitor, in kidney cancer and its paired normal kidney. Immunohistochemistry with automated batch staining and morphometry using digital pathology were used to compare ICAD in 121 RCC specimens with their paired normal kidney tissue. Tissue microarray of formalin-fixed, paraffin-embedded archival tissue was used. Intensity and localisation of ICAD were compared between normal and cancer samples, and against grading within the cancers. The results demonstrated that, in this cohort, ICAD was highly expressed in the proximal tubular epithelium of normal kidney, and significantly decreased in clear cell RCC tissue (p < 0.05) as well as other subtypes of RCC (p < 0.01) compared with normal kidney. There was a tendency towards nuclear localisation of ICAD in clear cell RCC, but not in other subtypes of RCC. No significant association was found between ICAD intensity and grade of RCC. In summary, down-regulation of ICAD occurs in RCC. ICAD normally inhibits DNA fragmentation and apoptosis; thus, its down-regulation was unexpected in a cancer known for its resistance to apoptosis. However, these RCC samples were from primary, not metastatic, RCC sites, and down-regulated ICAD may be part of a progressive pathway that promotes RCC metastasis.
Bcl-2 is an anti-apoptotic protein belonging to a family of proteins that act as regulators of apoptosis in mammalian cells. Bcl-2 expression has previously been reported in normal breast ductal cells and its involvement in the hormonal regulation of hyperplasia and involution was further suggested, and it was thought to be expressed through hormonedependent pathways. Bcl-2 is a cytoplasmic oncoprotein which is highly expressed in human solid tumours. In breast cancer cells, however, Bcl-2 expression is down regulated, the exact mechanism and the effects of which are not clearly defined, as bcl-2 expression appears to be inversely correlated with the presence of p53 mutations. This work aimed at investigating the expression of bcl-2 in invasive ductal carcinoma of the breast utilizing an immunohistochemistry assay as well as studying the clinical correlations of bcl-2. Bcl-2 was detected in 43.7% of 382 invasive ductal carcinoma study cases. Its expression correlated positively, with lower age of patients, higher histological grades, large tumour sizes, estrogen receptor positivity and progesterone receptor negativity. However, the statistical correlations were weak. With the data obtained, it was found that the expression of bcl-2 correlated with unfavourable prognoses. Furthermore, bcl-2 detection alone may not be very helpful in consolidating a clinical diagnosis.
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.
Cynaroside is a flavonoid, isolated from several species belonging to the Apiaceae, Poaceae, Lamiaceae, Solanaceae, Zingiberaceae, Compositae and other families and it can be extracted from seeds, roots, stems, leaves, barks, flowers, fruits, aerial parts, and the whole plant of these species. This paper discloses the current state of knowledge on the biological/pharmacological effects and mode of action to better understand the numerous health benefits of cynaroside. Several research works revealed that cynaroside could have beneficial effects on various human pathologies. Indeed, this flavonoid exerts antibacterial, antifungal, antileishmanial, antioxidant, hepatoprotective, antidiabetic, anti-inflammatory, and anticancer effects. Additionally, cynaroside exhibits its anticancer effects by blocking MET/AKT/mTOR axis by decreasing the phosphorylation level of AKT, mTOR, and P70S6K. For antibacterial activity, cynaroside reduces biofilm development of Pseudomonas aeruginosa and Staphylococcus aureus. Moreover, the incidence of mutations leading to ciprofloxacin resistance in Salmonella typhimurium was reduced after the treatment with cynaroside. In addition, cynaroside inhibited the production of reactive oxygen species (ROS), which reduced the damage to mitochondrial membrane potential caused by hydrogen peroxide (H2O2). It also enhanced the expression of the anti-apoptotic protein Bcl-2 and lowered that of the pro-apoptotic protein Bax. Cynaroside abrogated the up-regulation of c-Jun N-terminal kinase (JNK) and p53 protein expression triggered by H2O2. All these findings suggest that cynaroside could be used to prevent certain human diseases.
Clinacanthus nutans is a medicinal plant recognised for its anticancer properties. We previously discovered that the C. nutans extract had the most potent inhibitory effect on MCF7 breast cancer cell and significantly induced apoptosis. However, there is a scarcity of studies demonstrating the molecular interactions of C. nutans-derived chemical compounds associated with apoptosis-related proteins. Therefore, the objective of this study was to determine the potential chemical compounds found in the C. nutans extract and examine their interactions with the targeted apoptotic proteins using molecular docking and molecular dynamic simulations. To address this objective, the compounds found in the SF2 extract of C. nutans were analysed using Gas Chromatography-Mass Spectrometry (GC-MS). The molecular interaction of the compounds with the targeted apoptotic proteins were determined using molecular docking and molecular dynamic simulations. GC-MS analysis revealed a total of 32 compounds in the SF2 extract. Molecular docking analysis showed that compound β-amyrenol had the highest binding affinity for MDM2-P53 (-7.26 kcal/mol), BCL2 (-11.14 kcal/mol), MCL1-BAX (-6.42 kcal/mol), MCL1-BID (-6.91 kcal/mol), and caspase-9 (-12.54 kcal/mol), whereas campesterol had the highest binding affinity for caspase-8 (-10.11 kcal/mol) and caspase-3 (-10.14 kcal/mol). These selected compounds were subjected to molecular dynamic simulation at 310 K for 100 ns. The results showed that the selected protein-ligand conformation complexes were stable, compact, and did not alter much when compared to the protein references. The findings indicate that β-amyrenol and campesterol are potentially significant compounds that might provide insight into the molecular interactions of the compounds with the apoptosis-related proteins.Communicated by Ramaswamy H. Sarma.
Cruciferous vegetables are a rich source of glucosinolates that have established anti-carcinogenic activity. Naturally-occurring glucosinolates and their derivative isothiocyanates (ITCs), generated as a result of their enzymatic degradation catalysed by myrosinase, have been linked to low cancer incidence in epidemiological studies, and in animal models isothiocyanates suppressed chemically-induced tumorigenesis. The prospective effect of isothiocyanates as anti-carcinogenic agent has been much explored as cytotoxic against wide array of cancer cell lines and being explored for the development of new anticancer drugs. However, the mechanisms of isothiocyanates in inducing apoptosis against tumor cell lines are still largely disregarded. A number of mechanisms are believed to be involved in the glucosinolate-induced suppression of carcinogenesis, including the induction of apoptosis, biotransformation of xenobiotic metabolism, oxidative stress, alteration of caspase activity, angiogenesis, histone deacytylation and cell cycle arrest. The molecular mechanisms through which isothiocyanates stimulate apoptosis in cancer cell lines have not so far been clearly defined. This review summarizes the underlying mechanisms through which isothiocyanates modify the apoptotic pathway leading to cell death.
Natural compounds have been demonstrated to lower breast cancer risk and sensitize tumor cells to anticancer therapies. Recently, we demonstrated that vernodalin (the active constituent of the medicinal herb Centratherum anthelminticum seeds) induces apoptosis in breast cancer cell-lines. The aim of this work was to gain an insight into the underlying anticancer mechanism of vernodalin using in vitro and in vivo model.
There has been a growing interest in naturally occurring compounds from traditional medicine with anti-cancer potential. Nigella sativa (black seed) is one of the most widely studied plants. This annual herb grows in countries bordering the Mediterranean Sea and India. Thymoquinone (TQ) is an active ingredient isolated from Nigella sativa. The anti-cancer effect of TQ, via the induction of apoptosis resulting from mitochondrial dysfunction, was assessed in an acute lymphocyte leukemic cell line (CEMss) with an IC50 of 1.5 µg/mL. A significant increase in chromatin condensation in the cell nucleus was observed using fluorescence analysis. The apoptosis was then confirmed by Annexin V and an increased number of cellular DNA breaks in treated cells were observed as a DNA ladder. Treatment of CEMss cells with TQ encouraged apoptosis with cell death-transducing signals by a down-regulation of Bcl-2 and up-regulation of Bax. Moreover, the significant generation of cellular ROS, HSP70 and activation of caspases 3 and 8 were also observed in the treated cells. The mitochondrial apoptosis was clearly associated with the S phase cell cycle arrest. In conclusion, the results from the current study indicated that TQ could be a promising agent for the treatment of leukemia.
Chlorella vulgaris (CV) has been reported to have antioxidant and anticancer properties. We evaluated the effect of CV on apoptotic regulator protein expression in liver cancer-induced rats. Male Wistar rats (200~250 g) were divided into eight groups: control group (normal diet), CDE group (choline deficient diet supplemented with ethionine in drinking water to induce hepatocarcinogenesis), CV groups with three different doses of CV (50, 150, and 300 mg/kg body weight), and CDE groups treated with different doses of CV (50, 150, and 300 mg/kg body weight). Rats were sacrificed at various weeks and liver tissues were embedded in paraffin blocks for immunohistochemistry studies. CV, at increasing doses, decreased the expression of anti-apoptotic protein, Bcl-2, but increased the expression of pro-apoptotic protein, caspase 8, in CDE rats, which was correlated with decreased hepatocytes proliferation and increased apoptosis as determined by bromodeoxy-uridine (BrdU) labeling and terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) assay, respectively. Our study shows that CV has definite chemopreventive effect by inducing apoptosis via decreasing the expression of Bcl-2 and increasing the expression of caspase 8 in hepatocarcinogenesis-induced rats.
In the field of nanotechnology, the use of various biological units instead of toxic chemicals for the reduction and stabilization of nanoparticles, has received extensive attention. Among the many possible bio resources, biologically active products from fungi and yeast represent excellent scaffolds for this purpose. Since fungi and yeast are very effective secretors of extracellular enzymes and number of species grow fast and therefore culturing and keeping them in the laboratory are very simple. They are able to produce metal nanoparticles and nanostructure via reducing enzyme intracellularly or extracellularly. The focus of this review is the application of fungi and yeast in the green synthesis of inorganic nanoparticles. Meanwhile the domain of biosynthesized nanoparticles is somewhat novel; the innovative uses in nano medicine in different areas including the delivery of drug, cancer therapy, antibacterial, biosensors, and MRI and medical imaging are reviewed. The proposed signaling pathways of nanoparticles induced apoptosis in cancerous cells and anti-angiogenesis effects also are reviewed. In this article, we provide a short summary of the present study universally on the utilization of eukaryotes like yeast and fungi in the biosynthesis of nanoparticles (NPs) and their uses.
The increasing and widespread use of synthetic food dyes raises health concerns and earlier reports suggest that certain food dyes might be harmful for human health. In this study, we have investigated the effect of three commonly used food dyes on human liver cell line, HepG2. Our findings suggest that these experimental food dyes significantly affect cell viability and this effect can be worsen in hyperglycemic condition. Accumulation of cellular fat was significantly higher in presence of these dyes. Expression pattern of the gene involved in regulating apoptosis suggests that that the observed cell death could be attributed to the activation of apoptotic pathway. These findings suggest that these experimental dyes might exert synergistic toxicity in hyperglycemia that need to be confirmed using suitable in vivo models.
The Warburg effect has immensely succored the study of cancer biology, especially in highlighting the role of mitochondria in cancer stemness and their benefaction to the malignancy of oxidative and glycolytic cancer cells. Mitochondrial genetics have represented a focal point in cancer therapeutics due to the involvement of mitochondria in programmed cell death. The mitochondrion has been well established as a switch in cell death decisions. The mitochondrion's instrumental role in central bioenergetics, calcium homeostasis, and translational regulation has earned it its fame in metastatic dissemination in cancer cells. Here, we revisit and review mechanisms through which mitochondria influence oncogenesis and metastasis by underscoring the oncogenic mitochondrion that is capable of transferring malignant capacities to recipient cells.
Kesan sitotoksik sebatian organostanum (IV) terhadap pelbagai sel kanser telah dikaji oleh para saintis di seluruh dunia.Dalam kajian ini,dua sebatian baru organostanum (IV) iaitu difenilstanum (IV) etilfenilditiokarbamat (DFEF) dan difenilstanum (IV) butilfenilditiokarbamat (DFBF) telah diuji kesan sitotoksiknya terhadap sel eritroleukemia, K562. Sel eritroleukemia, K562 merupakan sel sasaran manakala, sel hepar Chang dan sel fibroblas V79 pula digunakan untuk menilai kesan kedua-dua sebatian ini terhadap sel bukan kanser. Kesan sitotoksik sebatian DFEF dan DFBF diuji menggunakan ujian asai 3-(4,5-dimetiltiazol-2-il)-2, 5-difeniltetrazolium bromida (MTT) dengan masa pendedahan 24 jam, 48 jam dan 72 jam pada kepekatan sebatian yang berbeza. Pemerhatian terhadap perubahan morfologi juga dilakukan menggunakan nilai IC50 yang diperolehi pada masa pendedahan seperti ujian asai MTT. Ujian sitotoksisiti telah menunjukkan sebatian DFEF dan DFBF adalah sangat toksik terhadap sel K562 dengan nilai IC50 kurang daripada 10 μM untuk ketiga-tiga masa pendedahan.Indeks pemilihan juga membuktikan bahawa kedua-dua sebatian memberikan kesan sitotoksik secara memilih terhadap sel K562 pada masa 48 jam dan 72 jam, tetapi pada masa 24 jam, sebatian ini bertindak secara tidak memilih terhadap sel K562 dan sel bukan kanser. Perubahan morfologi yang diperhatikan adalah menyerupai ciri-ciri apoptosis seperti pengecutan sel dan pembentukan jasad apoptotik dan juga nekrosis seperti sel lisis. Kesimpulannya, sebatian difenilstanum (IV) alkilfenilditiokarbamat berpotensi untuk dibangunkan sebagai agen antileukemia tetapi mekanisma khusus tindakan sebatian ini terhadap sel K562 perlu dikaji pada masa akan datang untuk menjelaskan potensi sebatian ini sebagai dadah antikanser yang baru.
One new indole alkaloid, reflexin A (1), and two known indoles, macusine B (2) and vinorine (3), were isolated from the bark of Rauvolfia reflexa. Their structures were elucidated by 1D and 2D NMR, UV, IR, and MS spectroscopic analyses. Compound 1 displayed anticancer activity against HCT-116 colon cancer cells with an IC50 value of 30.24 ± 0.75 µM. The results implied that the newly isolated 1 induced apoptosis in HCT-116 cells, suggesting its possible role as an anticancer agent. In vivo acute toxicity study was performed on compound 1 to evaluate its safety profile.
Tricyclohexylphosphanegold(I) n-mercaptobenzoate (n = 2, 3, 4) labelled as 1-3 were previously reported to significantly suppress thioredoxin reductase (TrxR) activities towards ovarian cancer cells, A2780, in vitro. Herein, we explored the role of 1-3 for their apoptosis inducing ability against A2780 cells. 1-3 exhibited IC50 values at 1.19 ± 0.03 µM, 2.28 ± 0.04 μM and 0.78 ± 0.01 μM, respectively, compared to cisplatin at 26.8 ± 0.15 µM. The compounds induced A2780 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by ROS production, cytochrome c release, caspases-3/7, -8, -9 and -10 activation, APAF1 and BAX upregulation as well as BCL2A1 and BCL2 genes' downregulation. In addition, the death mode of 1-3 was also mediated via death receptor extrinsic pathway manifested by FAS, FASL, FADD, and TNFR1 genes' upregulation via Human Rt PCR analysis. In addition, 1-3 significantly caused A2780 arrest at S phase, which was associated with the upregulation of TP53, E2F1, RB1 and CDKN1A upregulation and downregulation of CDK1, CDK4, CDC25A and CDC25C genes. Based on these promising results, these phosphanegold(I) thiolate derivatives could act as feasible candidates for further advanced in vivo ovarian cancer studies to develop novel chemotherapeutic agents derived from metal-based agents.