Figure - available from: Apoptosis
This content is subject to copyright. Terms and conditions apply.
The intrinsic pathway of apoptotic cell death is controlled by the BCL-2 protein family. This pathway is activated in response to various stress stimuli, such as oncogene activation or DNA damage. This causes an increase in the levels of the BH3-only proteins (e.g., PUMA, NOXA, BIM, BID, BAD) through diverse transcriptional as well as post-transcriptional processes. For example, the genes for PUMA and NOXA are directly transcriptionally activated by the tumour suppressor TP53/TRP53 (indicated in the dashed red box). The BH3-only proteins bind to the pro-survival BCL-2 proteins (e.g., BCL-2, BCL-XL, MCL-1) with high affinity. This unleashes the pro-apoptotic effector proteins BAK and BAX from their restraint by the pro-survival BCL-2 family members. The effectors of apoptosis, BAX and BAK, are also reported to be activated directly by certain BH3-only proteins, such as PUMA, BIM, and t-BID (the caspase activated form of BID). The activation of BAX and BAK allows these proteins to oligomerise and form pores in the outer mitochondrial membrane. This results in outer mitochondrial membrane permeabilisation (MOMP) causing release of cytochrome c from the space between the inner and the outer mitochondrial membranes into the cytoplasm. Upon release into the cytosol, cytochrome c drives the formation of a heptameric complex of the apoptotic protease activating factor 1 (APAF-1), called the apoptosome, which triggers the caspase cascade that causes the ordered demolition of the cells undergoing apoptosis
Source publication
Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in di...
Citations
... Bcl-2 is a well-established anti-apoptotic protein; Bcl-2 was involved in caspase-3 initiated apoptosis. Besides, the increase in the Bax/Bcl-2 ratio promotes apoptotic events including the up-regulation of caspase 3/9 and the consequent degradation of intracellular substrates [65]. Survivin is a vital member of the inhibitor of apoptosis protein family (IAP) where it suppresses apoptosis and enhances cell division. ...
Background
Breast cancer is the most common type of cancer diagnosed in women. Finding novel therapeutic agents with significant cytotoxic action and minimal adverse impact on normal cells becomes crucial. Today, natural anticancer agents present an unconventional method of treating cancer, either as a curative or preventative agent, with considerable concern for marine organisms.
Methods
The anticancer effect of the alcoholic extract of different Red Sea Seagrasses on MCF-7 human breast cancer cell line has been investigated. Seagrasses were collected from Wadi El Gamal, Red Sea and extracted. Qualitative HPLC analysis was performed on the extracts for the identification of their active biomarkers. This study was aimed to explore the cytotoxic impact of Thalassia hemprichii (Ehren.) and Enhalus acoroides (L.f.) Royle on MCF-7 and their mode of action. Their anti-proliferative effects on cancer cells were performed using Neutral red assay. On the other hand, their apoptotic effect and their capacity to induce cell cycle arrest were investigated by flow cytometry assay. The effect of Seagrasses on the mitochondrial membrane potential (ΔψM) was studied by using JC-1 mitochondrial membrane potential assay kit in Seagrasses treated cancer cells to Δψ Caspases 3/7activity was examined using the colorimetric method. Gene expression analysis and quantitative real time RT-PCR for the sea grasses on MCF-7 was performed. Immune-blotting technique for Bcl-2 and p53 was investigated.
Results
HPLC analysis demonstrated that the extracts contained mainly flavonoids and polyphenols such as Caffeic acid, Chlorogenic acids, catechin and kaempferol that might be responsible for these anticancer effects. Seagrasses alcoholic crude extract markedly suppressed the growth and expansion of MCF-7 cells concentration-dependently with no toxicity against normal human skin fibroblast HSF. Thalassia hemprichii and Enhalus acoroides trigger mode of cell death primarily via apoptosis as confirmed by the flow cytometry. Additionally, they have ability to induce G0/S cell cycle arrest in MCF-7. The data showed the depletion in mitochondrial membrane potential (ΔψM) in the treated cells dose-dependently Caspases 3/7activities markedly increased following 24 h treatment. Finally, Gene expression analysis showed a marked reduction in Bcl-2, Survivin and CDC2 gene expression levels and a significant increase in the expression of p53 and CC2D1A as compared to control cells.
Conclusion
In summary, the Methanolic extract of seagrass, Thalassia hemperchii and Enhalus ocoroides are able to induce concentration-dependent cytotoxic effects in human MCF-7 cells through intrinsic pathway of apoptosis in MCF-7 cells. This study reveals the beneficial importance of sea grasses as a source of anticancer agents. Further in vivo study is recommended for the active isolated biomolecules.
... The results of western blotting showed that DXR + RGin induced Nrf2 activation and promoted the expression of HO-1 and Bcl2. These molecules contribute to the antioxidant effects and inhibition of apoptosis [37,38]. The antioxidant effect of RGin can be attributed to an increase in HO-1 expression through the activation of Nrf2 [39][40][41]. ...
Background
Doxorubicin (DXR) is an effective chemotherapeutic agent. DOX-induced cardiomyopathy (DICM), a major limitation of DXR, is a complication with limited treatment options. We previously reported that Red Ginseng (steamed and dried the root of Panax Ginseng cultivated for over six years; RGin) is beneficial for the treatment of DICM. However, the mechanism underlying the action of RGin remains unclear. In this study, we investigated the mechanism of action underlying the efficacy of RGin in the treatment of DICM.
Methods
Four-week-old DBA/2 mice were divided into: vehicle, DXR, RGin, and DXR + RGin (n = 10/group). Mice were treated with DXR (4 mg/kg, once a week, accumulated 20 mg/kg, i.p.) or RGin (0.5 g/kg, three times a week, i.p.). To evaluate efficacy, the survival rate and left ventricular ejection fraction (LVEF) were measured as a measure of cardiac function, and cardiomyocytes were subjected to Masson trichrome staining. To investigate the mechanism of action, western blotting was performed to evaluate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1, transferrin receptor (TfR), and other related proteins. Data were analyzed using the Easy R software. Between-group comparisons were performed using one-way analysis of variance and analyzed using a post-hoc Tukey test. Survival rates were estimated using the Kaplan–Meier method and compared using the log-rank test. P < 0.05 was considered statistically significant in all analyses.
Results
RGin treatment prolongs survival and protects against reduced LVEF. In the DXR group, Nrf2 was not activated and cell death was accelerated. Furthermore, there was an increase in the TfR levels, suggesting abnormal iron metabolism. However, the DXR + RGin group showed activation of the Nrf2 pathway and suppression of myocardial cell death. Furthermore, there was no increase in TfR expression, suggesting that there were no abnormalities in iron metabolism. Therefore, the mechanism of action of RGin in DICM involves an increase in antioxidant activity and inhibition of cell death through activation of the Nrf2 pathway.
Conclusion
RGin is a useful therapeutic candidate for DICM. Its efficacy is supported by the activation of the Nrf2 pathway, which enhances antioxidant activity and inhibits cell death.
... This cascade leads to mitochondrial permeabilization, release of cytochrome-c, and activation of caspases, which initiates apoptosis (12). Maintaining the balance of Bcl-2 proteins is critical for apoptosis induction, thus strategies to modulate their expression or interactions hold potential anticancer utility (13)(14)(15)(16). The first generation of Bcl-2 family inhibitors, designed as BH3 mimetics, included the highly selective Bcl-2 inhibitor ABT-199 (venetoclax), which was approved by the FDA for treatment of hematological malignancies, either as a standalone therapy or in combination. ...
Apoptosis, or programmed cell death, plays a critical role in maintaining tissue homeostasis by eliminating damaged or abnormal cells. Dysregulation of apoptosis pathways is a hallmark of cancer, allowing malignant cells to evade cell death and proliferate uncontrollably. Targeting apoptosis pathways has emerged as a promising therapeutic strategy in cancer treatment, aiming to restore the balance between cell survival and death. In this context, the MDM2 inhibitor alrizomadlin, the Bcl-2/Bcl-xL inhibitor pelcitoclax, and the IAP family inhibitor dasminapant were evaluated both individually and in combination with standard of care and investigational anticancer small molecules with a spheroid model of solid tumors. The multi-cell type tumor spheroids were grown from endothelial cells and mesenchymal stem cells combined with human malignant cells that were either established or patient-derived cell lines from the NCI Patient-Derived Models Repository. The malignant cell lines were derived from a range of solid tumors including uterine carcinosarcoma, synovial sarcoma, rhabdomyosarcoma, soft tissue sarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor (MPNST), pancreas, ovary, colon, breast, and small cell lung cancer. Interactions were observed from combinations of the apoptosis pathway targeted agents. Additionally, interactions were observed from combinations of the apoptosis pathway targeted agents with other agents, including PARP inhibitors, the XPO1 inhibitor eltanexor, and the PI3K inhibitor copanlisib. Enhanced activity was also observed from combinations of the apoptosis pathway targeted agents with MAPK pathway targeted agents, including the MEK inhibitor cobimetinib as well as adagrasib and MRTX1133, which specifically target the KRAS G12C and G12D variants, respectively.
... The genes that encode the BH3-only proteins PUMA and NOXA are transcriptionally amplified by the tumour suppressor TP53. Although the importance of BIM regulation by the FOXO [59] transcription of the BCL2L11 gene, encoding BIM, has been revealed to be synchronized by FOXO3a, c-MYC, NF-Y, SMAD1/3, RUNX1-3, c-Jun, and RELA. ...
In recent years, a cancer research trend has shifted towards identifying novel therapeutic compounds from natural assets for the management of cancer. In this study, we aimed to assess the cytotoxic activity of Kigelia Africana (KA) extracts on breast cancer (MDA-MB-231 and MCF-7) and noncancerous kidney cells (HEK-293T) to develop an efficient anticancer medication. We used gas chromatography mass spectrometry (GC-MS to analyze the constituents of EKA and HKA extracts meanwhile the crystal violet and the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assays were used to examine the possible cytotoxic effects of plant extracts on our cancer cell lines along with non-cancerous control. The quantitative real-time PCR (RT-PCR) was run on cell samples to evaluate the differential expression of cell proliferative markers of cancer (BCL-2 and TP53). These phytochemicals have been reported to have binding affinity for some other growth factors and receptors as well which was evaluated by the in-silico molecular docking against Bcl2, EGFR, HER2, and TP53. Our Morphological observation showed a significant difference in the cell morphology and proliferation potential which was decreased under the effect of plant extracts treatment as compared to the control samples. The ethanol extract exhibited a marked antiproliferative activity towards MDA-MB-231 and MCF-7 cell lines with IC50 = 20 and 32 μg/mL, respectively. Quantitative RT-PCR gene expression investigation revealed that the IC50 concentration of ethanolic extract regulated the levels of mRNA expression of apoptotic genes. With the target and active binding site amino acids discovered in the molecular docking investigation, TP53/Propanoic acid, 3-(2, 3, 6-trimethyl-1, 4-dioxaspiro [4.4] non-7-yl)-, methyl ester (-7.1 kcal/mol) is the best-docked ligand. The use of this plant in folk remedies justifies its high in vitro anti-cancer capabilities. This work highlights the role of phytochemicals in the inhibition of cancer proliferation. Based on all these findings, it can be concluded that EKA extract has promising anti-proliferative effect on cancerous cells but more study is required in future to further narrow down the active ingredients of total crude extract with specific targets in cancer cells.
... Execution of cell death is modulated by the balance of pro-and anti-apoptotic proteins. The activity of antiapoptotic proteins belonging to the BCL family is recognized as one of the mechanisms contributing to cancer development and therapy resistance [132]. Targeting anti-apoptotic proteins is one of the leukaemia treatment strategies. ...
Post-transcriptional regulation by RNA binding proteins can determine gene expression levels and drive changes in cancer cell proteomes. Identifying mechanisms of protein-RNA binding, including preferred sequence motifs bound in vivo, provides insights into protein-RNA networks and how they impact mRNA structure, function, and stability. In this review, we will focus on proteins that bind to AU-rich elements (AREs) in nascent or mature mRNA where they play roles in response to stresses encountered by cancer cells. ARE-binding proteins (ARE-BPs) specifically impact alternative splicing, stability, decay and translation, and formation of RNA-rich biomolecular condensates like cytoplasmic stress granules (SGs). For example, recent findings highlight the role of ARE-BPs – like TIAR and HUR – in chemotherapy resistance and in translational regulation of mRNAs encoding pro-inflammatory cytokines. We will discuss emerging evidence that different modes of ARE-BP activity impact leukaemia and lymphoma development, progression, adaptation to microenvironment and chemotherapy resistance.
... There are two main pathways mediated by the process of programmed cell death activation: the extrinsic and the interstice pathways, both of which aim to stimulate the death of the damaged cells (2) the membranes of the bcl-2 family of proteins, which divide into pro-apoptotic and anti-apoptotic membranes, have an essential role in controlling apoptosis through their membranes that either stimulate or inhibit apoptosis (3). The abnormality of the anti-apoptotic membrane of the bcl-2 family or the defect of the pro-apoptotic membrane of the bcl-2 family membrane is commonly found in a variety of cancers (4). The bcl-2 gene belongs to the bcl-2 family and has an antiapoptotic function located on chromosome 18. ...
Apoptosis is a highly regular process of programmed cell death to remove unwanted and
damaged cells. This process occurs due to several stimulations, some of them external, such as DNA
damage exposed to UV and toxin and bacteria or virus infection, and also some external stimulation, like
the absence of growth hormone apoptosis. Any defect in the process of apoptosis has an association with
many diseases, like cancer and autoimmune disorders. The BCL-2 and BAX genes belong to the BCL-2
family. These genes regulate the process of program cell death by inhabiting the process of apoptosis or
directing the cell toward death. Leukemia is the most common type of blood cancer in children younger
than 15. The characteristics by rapid or slow proliferation of cancer cells depend on the type of
leukemia.The objectives of this study are the determination of the genetic variation and detection of the
new mutation of BAX and BCL-2 in patients suffering from leukemia in Mosul city.According to the
following study, the proportion of kids with leukemia who observed the wild genotype was (20), the
proportion of mutant genotypes was (30), and the proportion of heterogeneous groups was 50 compared
with the healthy control group. 70% for wild genotype, 20% for the heterogeneous, and 10% for the
mutant genotype.
... This disruption can arise from various sources, including genetic mutations, gene amplifications, and aberrant protein expression. 143 A classic example is chronic lymphocytic leukemia (CLL), where the common overexpression of Bcl-2 inhibits apoptosis, contributing to the survival and resistance of CLL cells. 144 Targeting Bcl-2 with specific inhibitors, such as venetoclax, has shown promise in clinical trials across CLL and other malignancies, underscoring the significance of understanding and targeting Bcl-2 family proteins in cancer treatment. ...
This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized by the Warburg effect, and the dynamic interplay between cancer cells and mitochondria. The role of cancer stem cells (CSCs) in treatment resistance and the regulatory influence of non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are studied. The chapter emphasizes future directions, encompassing advancements in immunotherapy, strategies to counter adaptive resistance, integration of artificial intelligence for predictive modeling, and the identification of biomarkers for personalized treatment. The comprehensive exploration of these hallmarks provides a foundation for innovative therapeutic approaches, aiming to navigate the complex landscape of cancer resistance and enhance patient outcomes.
... Consequently, researchers have explored the potential of targeting Bcl-2 as a therapeutic approach for colorectal cancer. [33] Specifically, the utilization of Bcl-2 inhibitors has been investigated in our study to hinder the antiapoptotic function of Bcl-2, thereby promoting the death of cancer cells. The human colorectal cancer cell line HCT-116 is widely utilized in research investigations pertaining to various aspects of colorectal cancer biology and therapeutic approaches. ...
A series of hybrid compounds containing both the imidazole ring and the hydrazone moiety have been synthesized. Synthesized compounds were characterized by various spectral techniques, including FT‐IR, ¹H‐NMR, ¹³C‐NMR, and HRMS. The compounds were evaluated for their antiproliferative activities on colorectal cancer cells HCT‐116 and HT‐29 in a time‐dependent manner. Among them, some compounds exhibited remarkable anti‐cancer activity with a less cytotoxic effect on non‐cancerous cell lines, especially HRK‐2 with IC50 value of 1.35±0.18 μM in HCT‐116 cells and HRK‐5 with IC50 value of 2.67±0.61 μM in HT‐29 cells. Investigations of colon cancer cell death were performed, and the most active compounds were found to trigger cell death via nuclear localization and induce S phase arrest of the colon cancer cell. Moreover, molecular modeling studies for the synthesized compounds was performed to predict their binding affinities toward the active site of BCL‐2. The findings of the molecular modeling investigations were highly consistent with those of the cytotoxicity results.
... Most members of the Bcl2 family have two structural homology regions through which different members can form heterodimers, and Bcl2 members are functional or functionally regulated through dimerization. Bcl2 can localize to mitochondria, stabilize the mitochondrial membrane potential, prevent apoptosis and protect cells (27). Dysfunction of the expression of Bcl2 family members can cause dysregulation of apoptosis and lead to the occurrence of diseases, including cancer and autoimmune diseases (27). ...
... Bcl2 can localize to mitochondria, stabilize the mitochondrial membrane potential, prevent apoptosis and protect cells (27). Dysfunction of the expression of Bcl2 family members can cause dysregulation of apoptosis and lead to the occurrence of diseases, including cancer and autoimmune diseases (27). Tumour cells have the ability to avoid apoptosis and survive, thus, apoptotic disorders can lead to malignant tumours (28). ...
Artesunate (ART), an antimalarial drug, has a broad spectrum of antitumour effects in cancer types such as esophageal and gastric cancer. However, evidence demonstrating the role of ART in cervical cancer cells is limited. In the present study, the inhibitory effect of ART on the growth of cervical cancer cells through the modulation of the cell cycle and apoptosis was investigated. The growth-inhibitory effect of ART on a cervical cancer cell line (SiHa) was detected using a Cell Counting Kit-8 assay after treatment with ART for 24 h, after which the half-maximal inhibitory concentration (IC50) was calculated. Using flow cytometry assays, apoptosis, the cell cycle, the levels of reactive oxygen species (ROS) and calcium (Ca²⁺) ions, as well as the mitochondrial membrane potential were evaluated in SiHa cells following treatment with ART for 24 and 48 h. The mRNA expression levels of Bcl2, Bcl-xl, (myeloid cell leukaemia 1) Mcl-1, Bcl2-like protein 11 (BIM), (Bcl2-related ovarian killer protein) Bok, Bax and (Bcl2 homologous antagonist/killer) Bak in SiHa cells were detected using reverse transcription-quantitative PCR. ART inhibited the growth of SiHa cells in a dose-dependent manner. The IC50 of ART in SiHa cells was 26.32 µg/ml. According to the IC50 value, 15, 30 and 100 µg/ml ART were selected for further experiments, and normal saline (0 µg/ml ART) was used as the control group. The results indicated that treatment with 15, 30 and 100 µg/ml ART for 24 and 48 h induced apoptosis, increased the levels of ROS, the levels of Ca²⁺ and the mRNA expression levels of BIM, Bok, Bax and Bak, but decreased the cell proliferation indices, the mitochondrial membrane potential and the mRNA expression levels of Bcl2, Bcl-xl and Mcl-1 in a dose- and time-dependent manner. In conclusion, ART inhibited the growth of SiHa cells and induced apoptosis via a mechanism associated with the regulation of Bcl2 family member expression, which was associated with the increase of the levels of ROS and Ca²⁺ and the reduction of the mitochondrial membrane potential.
... Key apoptotic regulators and signaling pathways mediate cellular cytotoxic response to platinum agents, and consequently, deficiencies within the pathways contribute to chemoresistance [88]. Platinum compounds can trigger apoptosis by extrinsic and intrinsic pathways [89][90][91]. Proapoptotic signaling activation leads to mitochondrial outer-membrane permeabilization and release of cytochrome C that triggers the activation of the caspase cascade [92]. Platinum-resistant tumors can express high levels of anti-apoptotic proteins or have defects in mitochondrial signaling [35]. ...
Ovarian cancer is a highly lethal form of gynecological cancer. This disease often goes undetected until advanced stages, resulting in high morbidity and mortality rates. Unfortunately, many patients experience relapse and succumb to the disease due to the emergence of drug resistance that significantly limits the effectiveness of currently available oncological treatments. Here, we discuss the molecular mechanisms responsible for resistance to carboplatin, paclitaxel, polyadenosine diphosphate ribose polymerase inhibitors, and bevacizumab in ovarian cancer. We present a detailed analysis of the most extensively investigated resistance mechanisms, including drug inactivation, drug target alterations, enhanced drug efflux pumps, increased DNA damage repair capacity, and reduced drug absorption/accumulation. The in-depth understanding of the molecular mechanisms associated with drug resistance is crucial to unveil new biomarkers capable of predicting and monitoring the kinetics during disease progression and discovering new therapeutic targets.
