Apoptotic Induction Research Articles

Mini-αA-Crystallin Stifled Melittin-Induced Haemolysis and Lymphocyte Lysis

Melittin, the most potent pharmacological ingredient of honey bee venom, induces haemolysis, lymphocyte lysis, long-term pain, localised inflammation, and hyperalgesia. In this study, efforts were made to subdue the melittin’s ill effects using a chaperone peptide called ‘mini-αA-crystallin’ (MAC) derived from eye lens αA-crystallin. Haemolytic test on human red blood cells, percentage viability, and DNA diffusion assay on Human peripheral blood lymphocytes (HPBLs) were performed with melittin in the presence or absence of MAC. Propidium iodide and Annexin V-FITC dual staining were performed to analyse quantitative levels of necrotic and apoptotic induction by melittin in the presence or absence of MAC on HPBLs using a flow cytometer. A computational study to find out the interactions between MAC and melittin was undertaken by modelling the structure of MAC using a PEP-FOLD server. The result showed that MAC inhibited melittin-induced lysis in nucleated (lymphocytes) and enucleated (RBC) cells. Flow cytometric analysis revealed a substantial increase in the necrotic and late apoptotic cells after treating HPBLs with melittin (4 µg/ml) for 24 h. Treatment with MAC at a 2:1 molar ratio prevented HPBLs from developing melittin-induced necrosis and late apoptosis. In the docking study, hydrogen, van der Waals, π-π stacking, and salt bridges were observed between the MAC and melittin complex, confirming a strong interaction between them. The MAC-melittin complex was stable during molecular dynamics simulation. These findings may be beneficial in developing a medication for treating severe cases of honeybee stings.

Jaboticaba (Myrciaria jaboticaba) peel extracts induce reticulum stress and apoptosis in breast cancer cells

Jaboticaba peel (Myrciaria jaboticaba) is a source of bioactive compounds. We investigated the anticancer activity of ethyl acetate extract (JE1) and hydroethanolic extract (JE2) of Jaboticaba peel against breast cancer. Both JE1 and JE2 inhibited clonogenic potential of MDA-MB-231 cells while JE1 was particularly effective in MCF7 cells. Anchorage-independent growth and cell viability was also inhibited by JE1 and JE2. In addition to growth inhibition, JE1 and JE2 could also inhibit migration and invasion of cells. Interestingly, JE1 and JE2 show selective inhibition towards certain breast cancer cells and biological processes. Mechanistic evaluations showed that JE1 induced PARP cleavage, BAX and BIP indicating apoptotic induction. An elevation of phosphorylated ERK was observed in MCF7 cells in response to JE1 and JE2 along with increased IRE-α and CHOP expression indicating increased endoplasmic stress. Therefore, Jaboticaba peel extracts could be potentially considered for further development for breast cancer inhibition.

Synthesis of Gingerol-loaded Uio-66 nanoparticles and its anti-cancer effect against gastric cancer cell line (AGS).

Gastric cancer is the world's fifth most prevalent cancer and its treatments are associated with issues. In this investigation, a UIO-66 nanoparticle was loaded with Gingerol (UIO-66-Gin) as a great drug carrier vehicle for chemotherapy of the AGS cancer cell lines. UIO-66-Gin characterization was performed using SEM, DLS and FTIR tests. The release profile of Gin from UIO-66 was also assessed. The cytotoxicity of UIO-66-Gin against AGS cells was assessed using MTT assay. Caspase3, Caspase9, Bax, and Bcl2 genes expression was evaluated via Real-time PCR and apoptosis rate was performed using flow-cytometry assay. Size analysis indicated the spherical shape of nano-formulation with the mean size of 174.3nm. Release analysis indicated that there was a 50% Gin release from the nanocarrier was reported in roughly 21h, which revealed the regulated release of bioactive compound from the UIO-66 formulation in PBS medium. After 48 and 72h, various concentration of both the Gin and UIO-66-Gin started to induce cytotoxicity in cancerous cells. However, the induction of cytotoxicity was higher in cells treated with UIO-66-Gin. UIO-66-Gin could induce the expression of pro-apoptotic (Bax, Caspase3, and Caspase9) genes and down-regulate the expression of Bcl2 as anti-apoptotic gene rather than other formulation. Flowcytometry results indicated that the elevation of apoptotic rate in cells treated with UIO-66-Gin was significantly higher than Gin treated cells. Our investigation revealed the potent anticancer effect and apoptotic induction ability of UIO-66-Gin against cancerous cells through altering the expression of genes involved in apoptosis.

Deciphering the modulatory role of apigenin targeting oncogenic pathways in human cancers.

Cancer is a complicated malignancy controlled by numerous intrinsic and extrinsic pathways. There has been a significant increase in interest in recent years in the elucidation of cancer treatments based on natural extracts that have fewer side effects. Numerous natural product-derived chemicals have been investigated for their anticancer effects in the search for an efficient chemotherapeutic method. Therefore, the rationale behind this review is to provide a detailed insights about the anticancerous potential of apigenin via modulating numerous cell signaling pathways. An ingestible plant-derived flavonoid called apigenin has been linked to numerous anticancerous potential in numerous experimental and biological studies. Apigenin has been reported to induce cell growth arrest and apoptotic induction by modulating multiple cell signaling pathways in a wider range of human tumors including those of the breast, lung, liver, skin, blood, colon, prostate, pancreatic, cervical, oral, and stomach. Oncogenic protein networks, abnormal cell signaling, and modulation of the apoptotic machinery are only a few examples of diverse molecular interactions and processes that have not yet been thoroughly addressed by scientific research. Thus, keeping this fact in mind, we tried to focus our review towards summarizing the apigenin-mediated modulation of oncogenic pathways in various malignancies that can be further utilized to develop a potent therapeutic alternative for the treatment of various cancers.

Cytotoxic action of the leaves of Uvaria chamae P.Beauv. and Dicliptera paniculata (Forssk.) I.Darbysh. from Nigeria mediated through intrinsic apoptotic pathway induction in four cancer cell lines

BackgroundOver the years, the morbidity and mortality due to cancer have continued to increase worldwide. Plants are well utilized in Nigeria ethno-medicine for cancer treatment. However, scientific evidence, particularly at the molecular level, has been lacking, and biodiversity loss is a threat. Aim of the studyThe cytotoxic activity of the leaves of six plants used in Nigeria ethno-medicine was investigated and the molecular pathway of cytotoxic action of two active extracts on four cancer cell lines (A549, RD, MCF-7, and HeLa) was also assessed. Materials and methodsCytotoxic activities of the plant extracts were assessed on breast (MCF-7), lung (A549), cervical (HeLa), adenocarcinoma and rhabdomyosarcoma (RD) cells using MTT cell viability assay in a time-dependent manner. The sandwich ELISA method was used to assess the protein expressions (Bcl-2, BAX, and executioner caspase 3) involved in the apoptotic pathway in cancer cells after treatment with cytotoxic extracts. UHPLC-MS/MS approach was used to analyze the possible bioactive phytochemicals of the cytotoxic plant extract. ResultsUvaria chamae and Dicliptera paniculata extracts displayed good cytotoxicity across all cell lines in a time- and concentration-dependent manner (CC50 <30 µg/mL). Increased pro-apoptotic BAX and lowered expression of anti-apoptotic Bcl-2 show the cytotoxic action of the two extracts followed the intrinsic apoptotic pathway compared to untreated cells. The increased expression of executioner caspase 3 indicated that the intrinsic apoptotic pathway was caspase-dependent. ConclusionThe anticancer potential of U. chamae and D. paniculata in this study validates the use of these plants in Nigerian ethno-medicine, highlighting apoptosis as a molecular pathway of their cytotoxicity.

GA-OH enhances the cytotoxicity of photon and proton radiation in HPV+ HNSCC cells.

Treatment-related toxicity following either chemo- or radiotherapy can create significant clinical challenges for HNSCC cancer patients, particularly those with HPV-associated oropharyngeal squamous cell carcinoma. Identifying and characterizing targeted therapy agents that enhance the efficacy of radiation is a reasonable approach for developing de-escalated radiation regimens that result in less radiation-induced sequelae. We evaluated the ability of our recently discovered, novel HPV E6 inhibitor (GA-OH) to radio-sensitize HPV+ and HPV- HNSCC cell lines to photon and proton radiation. Radiosensitivity to either photon or proton beams was assessed using various assays such as colony formation assay, DNA damage markers, cell cycle and apoptosis, western blotting, and primary cells. Calculations for radiosensitivity indices and relative biological effectiveness (RBE) were based on the linear quadratic model. Our results showed that radiation derived from both X-ray photons and protons is effective in inhibiting colony formation in HNSCC cells, and that GA-OH potentiated radiosensitivity of the cells. This effect was stronger in HPV+ cells as compared to their HPV- counterparts. We also found that GA-OH was more effective than cetuximab but less effective than cisplatin (CDDP) in enhancing radiosensitivity of HSNCC cells. Further tests indicated that the effects of GA-OH on the response to radiation may be mediated through cell cycle arrest, particularly in HPV+ cell lines. Importantly, the results also showed that GA-OH increases the apoptotic induction of radiation as measured by several apoptotic markers, even though radiation alone had little effect on apoptosis. The enhanced combinatorial cytotoxicity found in this study indicates the strong potential of E6 inhibition as a strategy to sensitize cells to radiation. Future research is warranted to further characterize the interaction of GA-OH derivatives and other E6-specific inhibitors with radiation, as well as its potential to improve the safety and effectiveness of radiation treatment for patients with oropharyngeal cancer.

Acute high-fat diet impairs macrophage-supported intestinal damage resolution.

Chronic exposure to high-fat diets (HFD) worsens intestinal disease pathology, but acute effects of HFD in tissue damage remain unclear. Here, we used short-term HFD feeding in a model of intestinal injury and found sustained damage with increased cecal dead neutrophil accumulation, along with dietary lipid accumulation. Neutrophil depletion rescued enhanced pathology. Macrophages from HFD-treated mice showed reduced capacity to engulf dead neutrophils. Macrophage clearance of dead neutrophils activates critical barrier repair and antiinflammatory pathways, including IL-10, which was lost after acute HFD feeding and intestinal injury. IL-10 overexpression restored intestinal repair after HFD feeding and intestinal injury. Macrophage exposure to lipids from the HFD prevented tethering and uptake of apoptotic cells and Il10 induction. Milk fat globule-EGF factor 8 (MFGE8) is a bridging molecule that facilitates macrophage uptake of dead cells. MFGE8 also facilitates lipid uptake, and we demonstrate that dietary lipids interfere with MFGE8-mediated macrophage apoptotic neutrophil uptake and subsequent Il10 production. Our findings demonstrate that HFD promotes intestinal pathology by interfering with macrophage clearance of dead neutrophils, leading to unresolved tissue damage.

Peimine Inhibits MCF-7 Breast Cancer Cell Growth by Modulating Inflammasome Activation: Critical Roles of MAPK and NF-κB Signaling.

Peimine (PM) is a bioactive compound obtained from Fritillaria. It has been documented that PM exhibits potent antitumor properties against multiple cancers. However, the antitumor properties of PM in breast cancer and its associated mechanisms have not been clarified. Proliferation and apoptosis of MCF-7 and MCF-10A cells were detected by CCK8, colony formation, and flow cytometry assays. Cytotoxicity was measured by Lactate dehydrogenase (LDH) leakage assay. The level of IL-1β and IL-18 were detected with ELISA kits. Western blotting and real-time Polymerase Chain Reaction were performed to analyze the expression of proteins and genes related to the NLRP3 inflammasome pathway and Endoplasmic reticulum stress. The doses of PM (5, 10, and 20 μM) inhibited cell viability significantly, apoptotic induction, and inflammasome activation in breast cancer cells in vitro. Inflammasome components were decreased, including the apoptosisassociated speck like protein containing a CARD (ASC) and NOD-like receptor pyrindomain-containing protein3 (NLRP3), as well as the inhibition of caspase-1 and interleukin-1β activation. Moreover, inflammasome inhibitors suppressed cell growth and induced apoptosis, implying that PM suppresses the growth of breast cancer cells through regulating inflammasome. Mechanistically, PM inhibited the activity of inflammasome by alleviating endoplasmic reticulum (ER) stress and by down-regulating the expression of multiple proteins in transcription factor nuclear factor- κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. These findings show that PM suppresses the growth of breast cancer cells by inhibiting inflammasome activation, to a certain extent, by primarily acting on the MAPK/NF-κB pathway's inactivation-dependent mechanisms.

Ponciri Fructus Immatarus Sensitizes the Apoptotic Effect of Hyperthermia Treatment in AGS Gastric Cancer Cells through ROS-Dependent HSP Suppression

Gastric cancer has been associated with a high incidence and mortality, accompanied by a poor prognosis. Given the limited therapeutic options to treat gastric cancer, alternative treatments need to be urgently developed. Hyperthermia therapy is a potentially effective and safe treatment option for cancer; however, certain limitations need to be addressed. We applied 43 °C hyperthermia to AGS gastric cancer cells combined with Ponciri Fructus Immaturus (PF) to establish their synergistic effects. Co-treatment with PF and hyperthermia synergistically suppressed AGS cell proliferation by inducing extrinsic and intrinsic apoptotic pathways. Additionally, PF and hyperthermia suppressed factors related to metastasis. Cell cycle arrest was determined by flow cytometry, revealing that co-treatment induced arrest at the G2/M phase. As reactive oxygen species (ROS) are critical in hyperthermia therapy, we next examined changes in ROS generation. Co-treatment with PF and hyperthermia increased ROS levels, and apoptotic induction mediated by this combination was partially dependent on ROS generation. Furthermore, heat shock factor 1 and heat shock proteins (HSPs) were notably suppressed following co-treatment with PF and hyperthermia. The HSP-regulating effect was also dependent on ROS generation. Overall, these findings suggest that co-treatment with PF and hyperthermia could afford a promising anticancer therapy for gastric cancer.

Apoptotic Induction in Human Cancer Cell Lines by Antimicrobial Compounds from Antarctic Streptomyces fildesensis (INACH3013)

The Antarctic Streptomyces fildesensis has been recognized for its production of antimicrobial compounds with interesting biological activities against foodborne bacteria and multi-resistant strains, but not for its potential antiproliferative activity and mechanisms involved. Two bioactive ethyl acetate extract (EAE) fractions were purified via thin-layer chromatography and High-Performance Liquid Chromatography (HPLC), showing that orange-colored compounds displayed antimicrobial activity against pathogenic bacteria even after shock thermal treatment. The UV–VIS features of the active compounds, the TLC assay with actinomycin-D pure standard, Fourier transform infrared (FTIR) spectra and the ANTISMASH analysis support the presence of actinomycin-like compounds. We demonstrated that S. fildesensis displays antiproliferative activity against human tumor cell lines, including human breast cancer (MCF-7), prostate cancer (PC-3), colon cancer (HT-29) and non-tumoral colon epithelial cells (CoN). The half-maximal effective concentrations (EC50) ranged from 3.98 µg/mL to 0.1 µg/mL. Our results reveal that actinomycin-like compounds of S. fildesensis induced apoptosis mediated by caspase activation, decreasing the mitochondrial membrane potential and altering the cell morphology in all tumoral and non-tumoral cell lines analyzed. These findings confirm the potential of the psychrotolerant Antarctic S. fildesensis species as a promising source for obtaining potential novel anticancer compounds.

In vitro and in silico studies of Neophytadiene; a diterpene isolated from Aeschynomene elaphroxylon (Guill. &amp;Perr.) Taub. as apoptotic inducer

In vitro and in silico studies of Neophytadiene; a diterpene isolated from Aeschynomene elaphroxylon (Guill. &amp;Perr.) Taub. as apoptotic inducer

Olive leaves extract alleviates inflammation and modifies the intrinsic apoptotic signal in the leukemic bone marrow.

Current anti-leukemic chemotherapies with multiple targets suffer from side effects. Synthetic drugs with huge off-target effects are detrimental to leukemic patients. Therefore, natural plant-based products are being increasingly tested for new anti-leukemic therapy with fewer or no side effects. Herein, we report the effect of ethanolic olive leaves extract (EOLE) on the K562 cell line and on the bone marrow (BM) of N-ethyl-N-nitrosourea (ENU)-induced leukemic mice. Using standard methodologies, we assessed viability, chromatin condensation, and induction of apoptosis in EOLE-treated K562 cells in-vitro. The anti-leukemic activity of EOLE was assayed by measuring ROS, levels of various cytokines, expression of iNOS and COX-2 gene, and changes in the level of important apoptosis regulatory and cell signaling proteins in-vivo. K562 cells underwent apoptotic induction after exposure to EOLE. In the BM of leukemic mice, EOLE therapy decreased the number of blast cells, ROS generation, and expression of NF-κB and ERK1/2. IL-6, IL-1β, TNF-α, iNOS, and COX-2 were among the inflammatory molecules that were down-regulated by EOLE therapy. Additionally, it decreased the expression of anti-apoptotic proteins BCL2A1, BCL-xL, and MCL-1 in the BM of leukemic mice. Chronic inflammation and anomalous apoptotic mechanism both critically contribute to the malignant transformation of cells. Inflammation in the tumor microenvironment promotes the growth, survival, and migration of cancer cells, accelerating the disease. The current investigation showed that EOLE treatment reduces inflammation and alters the expression of apoptosis regulatory protein in the BM of leukemic mice, which may halt the progression of the disease.

Identification of new benzimidazole-triazole hybrids as anticancer agents: multi-target recognition, in vitro and in silico studies

Multi-target inhibitors represent useful anticancer agents with superior therapeutic attributes. Here in, two novel series of benzimidazole-triazole hybrids were designed, synthesised as multi-target EGFR, VEGFR-2 and Topo II inhibitors, and evaluated for anticancer activity. Compounds 5a and 6g were the most potent analogues against four cancer cell lines, HepG-2, HCT-116, MCF-7 and HeLa, and were further evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 5a was especially good inhibitor for EGFR (IC50 = 0.086 µM) compared to Gefitinib (IC50 = 0.052 µM), moderate VEGFR-2 inhibitor (IC50 = 0.107 µM) compared to Sorafenib (IC50 = 0.0482 µM), and stronger Topo II inhibitor (IC50 = 2.52 µM) than Doxorubicin (IC50 = 3.62 µM). Compound 6g exhibited moderate EGFR and VEGFR-2 inhibition and weaker Topo II inhibition. DNA binding assay, cell cycle analysis, apoptotic induction, molecular docking, and physicochemical studies were additionally implemented to explore the plausible mechanism of the active compounds.

Luminescent 11-{Naphthalen-1-yl}dipyrido[3,2-a:2',3'-c]phenazine-Based Ru(II)/Ir(III)/Re(I) Complexes for HCT-116 Colorectal Cancer Stem Cell Therapy.

Due to a number of unpleasant considerations, marketed drugs have steadily lost their importance in the treatment of cancer. In order to find a viable cancer cell diagnostic agent, we therefore focused on metal complexes that displayed target adequacy, permeability to cancer cells, high standard water solubility, cytoselectivity, and luminescent behavior. In this aspect, luminescent 11-{naphthalen-1-yl} dipyrido [3,2-a:2',3'-c] phenazine based Ru(II)/Ir(III)/Re(I) complexes have been prepared for HCT-116 colorectal cancer stem cell therapy. Our study successfully established the possible cytotoxicity of IrL complex at different doses on HCT-116 colorectal cancer stem cells (CRCSCs). Additionally, an immunochemistry analysis of the complex IrL showed that the molecule was subcellularly localized in the nucleus and other regions of the cytoplasm, where it caused nuclear DNA damage and mitochondrial dysfunction. The level of BAX and Bcl-2 was further quantified by qRT-PCR. The expression of proapoptotic BAX showed increased expression in the complex IrL-treated cell compared to the control, indicating the potential of complex IrL for apoptotic induction. Upon further validation, complex IrL was developed as an inhibitor of autophagy for the eradication of cancer stem cells.

Oroxylum indicum Vent Root Bark Extract Inhibits the Proliferation of Cancer Cells and Induce Apoptotic Cell Death

Oroxylum indicum Vent is a medium-sized deciduous tree that belongs to the family Bignoniaceae. The roots of this tree are used as one of the ten ingredients to prepare the Dasamula formulation in the Ayurvedic system of medicine in India. Although traditional uses are attributed to the medicinal plant, there are limited scientific data on its potential. The present study thus analyzed the cytotoxic and apoptotic potential of the plant against different cancer cells. MTT assay was used to determine cytotoxicity using HeLa, HCT 15, and MDA-MB-231 cells, with the IC50 values, revealed at concentrations of 92.43, 133.0, and 112.84 µg/mL respectively. However, the extract was less toxic to non-cancer cells. HeLa cells further treated with OIM were subjected to flow cytometric analysis for studying the cell cycle stages. When untreated cells at G1 phase were found at a relative percentage of 71.9%, it increased to 79.3 and 86% with OIM treatment at concentrations of 50 and 100 µg/mL; cells in the S phase decreased from 10.3 to 8.2 and 7.5%, concluding the arrest of the cell cycle at G1 phase. With further study of apoptotic morphology with dual acridine orange–ethidium bromide staining and Annexin–Hoechst staining, cells at early and late apoptotic stages were observed with OIM treatment at 100 µg/mL concentration. Although such effects were noticed with OIM treatment, it could not be concluded that the extract had remarkable anti-proliferative effects, since the small changes noticed in cell cycle arrest and apoptotic induction were attained at a high concentration of OIM 100 µg/mL. The biological activities of plants and their extracts are attributed to the presence of multifarious compounds present in them. LC-MS Q-TOF analysis confirmed the presence of biochanin A and baicalein in OIM. HPLC-based quantification of baicalein and chrysin was shown to be 3.36 and 1.11 mg/gram dry weight. To conclude, the above results suggest that the root bark of O. indicum has a broad spectrum of biological activities, including anticancer and apoptotic properties.

Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways.

Grapevine (Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.

Co-targeting BCL-XL and MCL-1 with DT2216 and AZD8055 synergistically inhibit small-cell lung cancer growth without causing on-target toxicities in mice

Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-XL and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities. We, therefore, aimed to develop an effective and safe strategy targeting these anti-apoptotic proteins with DT2216 (our platelet-sparing BCL-XL degrader) and AZD8055 (an mTOR inhibitor) to avoid associated on-target toxicities while synergistically optimizing tumor response. Through BH3 mimetic screening, we identified a subset of SCLC cell lines that is co-dependent on BCL-XL and MCL-1. After screening inhibitors of selected tumorigenic pathways, we found that AZD8055 selectively downregulates MCL-1 in SCLC cells and its combination with DT2216 synergistically killed BCL-XL/MCL-1 co-dependent SCLC cells, but not normal cells. Mechanistically, the combination caused BCL-XL degradation and suppression of MCL-1 expression, and thus disrupted MCL-1 interaction with BIM leading to an enhanced apoptotic induction. In vivo, the DT2216 + AZD8055 combination significantly inhibited the growth of cell line-derived and patient-derived xenografts and reduced tumor burden accompanied by increased survival in a genetically engineered mouse model of SCLC without causing appreciable thrombocytopenia or other normal tissue injuries. Thus, these preclinical findings lay a strong foundation for future clinical studies to test DT2216 + mTOR inhibitor combinations in a subset of SCLC patients whose tumors are co-driven by BCL-XL and MCL-1.

Insights into the impact of spermidine in reducing salinity stress in Gerbera jamesonii

Therapeutic potential of harmaline, a novel alkaloid, against cervical cancer cells in vitro: Apoptotic induction and DNA interaction studyParomita Bhattacharjee, Sarita Sarkar, Tapas Ghosh, Kakali Bhadra

Naphthoyl benzhydrazine-decorated binuclear arene Ru(II) complexes as anticancer agents targeting human breast cancer cells.

Breast cancer is the most dangerous type in women and its fatality rate has increased over the past decade. To develop more potent and target-specific breast cancer drugs, six arene ruthenium(II) complexes (1-6) containing naphthoyl benzhydrazine ligands (NL1-NL3) were synthesized and characterized by analytical and spectroscopic (infrared, UV-visible, NMR and HR-MS) methods. The SC-XRD analysis of 1 and 6 demonstrates the bis N^O bidentate binding nature of ligands to ruthenium ions and a pseudo-octahedral geometry around the Ru(II) ion. Solution stability studies using UV-Vis spectroscopy evidenced the instantaneous hydrolysis of the complexes to form monoaquated species in a solution of 1 : 9 (v/v) DMSO/phosphate buffer. All the complexes were screened for their in vitro antiproliferative activities against different human breast cancer cells, including MCF-7, SkBr3, MDA-MB-468, MDA-MB-231, and non-cancerous HEK-293 cells, by an MTT assay, and they displayed good cancer cell growth inhibitory capacity with low IC50 values. Notably, complexes 2 and 5 comprising methoxy and p-cymene groups exhibited excellent cytotoxicity towards SkBr3 cells compared to clinical drug cisplatin. AO-EB and HOECHST-33342 staining assays revealed apoptotic morphological changes in complex-treated cancer cells. Further, reactive oxygen species and mitochondrial membrane potential assays validated that the complexes induce apoptotic cell death via an intrinsic mitochondrial pathway with ROS production. In addition, the apoptotic induction and the quantification of late apoptosis were established with the aid of western blot and flow cytometry analysis, respectively.

The Role of NF-κB p65 in White Tea Aqueous Extract-Induced Cancer Cell Apoptosis

White tea encompasses a number of teas unique to eastern Fujian in China. Although white tea extracts have been reported to result in cancer cell apoptosis, to date, few studies have evaluated the mechanism of such apoptotic induction. A transcription factor that plays a critical role in cell apoptosis, NF-κB p65, is also likely critical by which white tea extracts induce cancer cell apoptosis. In this study, white tea aqueous extract (WTAE) was added to BEL-7402 and Hela cell media and NF-κB p65 activation was evaluated using western blotting and immunofluorescence. Results revealed that the phosphorylation of IKBα and p65 decreased in both cell lines after WTAE treatment. And the nuclear translocation of NF-κB p65 in both cell lines was also reduced with the WTAE treatment. NF-κB p65 inhibition was noted to accelerate apoptosis. Our findings suggest that NF-κB p65 was an important modulator in WTAE-induced apoptotic signal transduction and it acted as a negative regulator of apoptotic induction in BEL-7402 and Hela cancer cell lines.