Apoptosis In Breast Research Articles

Morchella conica, Morchella esculenta and Morchella delicosa Induce Apoptosis in Breast and Colon Cancer Cell Lines via Pro-apoptotic and Anti-apoptotic Regulation.

To explore the potential apoptotic mechanisms of 3 Morchella extracts (Morchella conica, Morchella esculenta and Morchella delicosa) on breast and colon cancer cell lines using apoptotic biomarkers. Human breast cell line (MCF-7) and colon cancer cell line (SW-480) were treated with methanol and ethanol extracts of 3 Morchella species with concentration ranging from 0.0625 to 2 mg/mL. After that their effects on gene expression of apoptosis related markers (pro-apoptotic markers including Bax, caspase-3, caspase-7, and caspase-9, and the antiapoptotic marker including Bcl-2) were determined using reverse transcription polymerase chain reaction. All Morchella extracts reduced breast and colon cancer cells proliferation at half inhibitory concentration (IC50) of 0.02 ±0.01 to 0.68 ±0.30 mg/mL. As expected, all Morchella extracts significantly increased gene expressions of Bax, caspase-3, caspase-7, and caspase-9 and downregulated the gene expression of Bcl-2 in MCF-7 and SW-480 cell lines (P<0.05). Morchella extracts demonstrated significant anti-proliferative activity against breast and colon cancer cell lines via an apoptosis induction mechanism. Anticancer activity of Morchella extracts and activation of apoptosis in breast and colon cancer cells suggest that it may be used to develop chemotherapeutic agents against cancer in future.

Enhanced Apoptotic Effects in MDA-MB-231 Triple-Negative Breast Cancer Cells Through a Synergistic Action of Luteolin and Paclitaxel.

According to reports on cancer incidence in 2020, breast cancer became the leading malignancy among women worldwide. This multistep disease involves genetic and environmental factors. Paclitaxel, a naturally occurring antimitotic substance, is a widely used chemotherapeutic drug for treating various human malignancies, including breast cancer. However, its major drawback is its extensive toxicity. This limitation can be mitigated through combination therapy with natural products like luteolin. Studies suggest that luteolin has anticancer properties, as it inhibits cancer cell growth and induces apoptosis in breast, lung, and colon cancers. This study aims to investigate the synergistic anticancer effects of combining luteolin and paclitaxel on breast cancer cells. Breast cancer cell line (MDA-MB-231) was utilized for this study. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was then conducted to check the cell viability. This was followed by a morphology study conducted under a phase contrast microscope. Morphological analysis revealed pronounced cell shrinkage and membrane blebbing, indicative of apoptosis when treated with the combination at their IC50 values. Gene expression results further confirmed the anticancer properties by showing significant downregulation of the B-cell lymphoma-2 (BCL-2) anti-apoptotic gene. These findings suggest that the luteolin-paclitaxel combination exerts a synergistic effect, enhancing anticancer activity in breast cancer cells. Reverse transcriptase polymerase chain reaction (RT-PCR) was done to analyze the genes involved in apoptosis. Finally, the data collected was statistically analyzed to confirm the reliability of the study. The combination of 1 μM/ml of paclitaxel and increasing concentrations of luteolin showed a great percentage of reduction in cell viability and the IC50 value of luteolin concentration was around 40 μM/ml. The morphology study revealed that the cancer cells showed shrinkage and blebbing on treatment with 40 μM/ml. At the same IC50 concentration, the combination of luteolin and paclitaxel resulted in a significant downregulation of BCL-2mRNA expression in breast cancer cells compared to luteolin alone. The combination of paclitaxel and luteolin has a synergistic effect on breast cancer cells and shows potential as a treatment for various cancers.Given these promising results, the paclitaxel and luteolin combination could be developed into a potent therapeutic strategy for treating various cancers. Future research should include in vivo studies to further assess the therapeutic potential and safety profile of this combination.

Molecular interactions between metformin and D-limonene inhibit proliferation and promote apoptosis in breast and liver cancer cells

BackgroundCancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative.Hypothesis/PurposeIn this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7.Study designAn integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene.MethodsWe applied a systems-based analysis to introduce a drug–target–pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis.ResultsThe mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22).ConclusionOur data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.

Noscapine and Apoptosis in Breast and Other Cancers.

Breast cancer is the second leading contributor to the age-standardized mortality rate, for both sexes and all ages worldwide. In Europe and the United States, it is the second leading cause of mortality, with an incidence rate of about 2.6 million cases per year. Noscapine, a well-known alkaloid used as a cough suppressant, demonstrated anti-tumor effects by triggering apoptosis in various cancer cell lines and has the potential to become another ally against breast, ovarian, colon, and gastric cancer, among other types of malignancy. Apoptosis plays a crucial role in the treatment of cancer. Noscapine affected BAX, CASP8, CASP9, NFKBIA, and RELA gene and protein expression in the MCF-7 and MDA-MB-231 cell lines. Gene expression was higher in tumor than in normal tissue, including the BAX expression levels in lung, ovary, endometrium, colon, stomach, and glioblastoma patients; BCL2L1 expression in endometrium, colon, and stomach patients; CASP8 gene expression levels in lung, endometrium, colon, stomach, and glioblastoma patients; RELA in colon, stomach, and glioblastoma patients; and NFKBIA in glioblastoma patients. It can be concluded that noscapine affected genes and proteins related to apoptosis in cancer cell lines and several types of cancer patients.

Anticancer Activity of Iso-Mukaadial Acetate on Pancreatic and Colon Cancer Cells.

Pancreatic cancer and colon cancer pose significant challenges in treatment, with poor prognoses. Natural products have long been explored for their potential as anticancer agents. Iso-mukaadial acetate has shown promise in inducing apoptosis in breast and ovarian cancer cells. The objective of this study was to investigate the effect of Iso-mukaadial acetate on pancreatic (MIA-PACA2) and colon (HT29) cancer cell lines. Pancreatic (MIA-PACA2) cancer cells, colon (HT29) cancer cells, normal embryonic kidney cells (HEK 293), and normal lung cells (MRC5) were cultured and treated with Iso-mukaadial acetate (IMA) for 24 hours. The viability assays were conducted using Alamarblue reagent and a real-time cell viability monitoring system, xCELLigence. The IC50 values were determined, followed by assessments of ATP production, caspase 3/7 activation, mitochondrial function, morphological changes using a light microscope, and gene expression changes via RT-PCR. This study indicates that Iso-mukaadial acetate exhibited concentration-dependent cytotoxic effects, slowing cellular proliferation in both cancer cell lines. Activation of the mitochondrial apoptotic pathway and caspase 3/7 suggests induction of apoptosis. Reduced ATP production and altered gene expression further support its anticancer properties. Morphological changes after treatment with Iso-mukaadial acetate showed apoptotic characteristics which may suggest that apoptosis was induced. According to the results obtained, Iso-mukaadial acetate shows potential as an anticancer agent, evidenced by its effects on cellular viability, mitochondrial function, ATP production, caspase activation, and gene expression in pancreatic and colon cancer cells. These findings highlight its promise for further investigation and potential in the development of therapeutic agents.

Synthetic Curcumin Analogs in the Treatment of Cancer: A Literature Review.

Treatment of cancer, one of the most fatal diseases in the present century, has become a topic of global concern. Unfavorable unintentional effects of chemotherapy and radiation treatments have been the main reasons for the research on the discovery of drugs with a broader spectrum of effectiveness and efficiency, with minimal side effects. Curcumin (diferuloylmethane) is a naturally occurring phenolic structure with anticancer properties through its inhibition of cell multiplication, metastasis, and prolongation of cell cycle suppression of apoptosis in various tumor cells. The primary restriction regarding the use of curcumin in cancer treatment is related to poor bioavailability and unfavorable pharmacokinetic profiles of curcumin due to its poor absorption rate, fast metabolism, and systemic elimination. A variety of ways have been proposed to overcome these limitations. With this background, the present study focuses on providing a comprehensive overview of the anticancer properties of curcumin derivatives and the synthesis of curcumin analogs with application to different types of cancers. The regulation of various target and signaling pathways is considered in various cancers, including breast, gastrointestinal, pancreatic, prostate, skin, and lung cancers. A review of the literature indicates that modifying the structure of curcumin through the substitution of the phenyl group and unsaturated carbon branch around the two main sites of oxygen can result in the improvement of physical and chemical properties, as well as the enhancement of physiological activities of the curcumin molecule and the anti-cancer activities of this polyphenol. Curcumin analogs demonstrate anticancer properties at multiple targets at different cell stages and by various signaling biochemical pathways. These include cytokines, transcription factors, growth factors, and modulation of genes involved in cellular proliferation and apoptosis in breast, gastrointestinal, skin, prostate, and lung cancers, thereby mitigating tumor progression.

Biological Properties of Extracts Obtained from In Vitro Culture of Plectranthus scutellarioides in a Cell Model.

Plectranthus scutellarioides (L.) R.Br. is a medicinal plant that has long been used in traditional medicine to treat conditions such as abscesses, ulcers, and ear and eye infections. It is known to have a wide range of biological properties, such as antibacterial, antioxidant, antifungal, anti-inflammatory, anti-diabetic and anti-cancer effects. In this study, we established in vitro cultures from both the aerial parts and roots of Plectranthus scutellarioides. Subsequently, we compared the basic phytochemical profile of the obtained extracts and conducted a biological analysis to assess their potential for inducing apoptosis in breast (MCF-7) and lung (A549) cancer cells. Phytochemical analysis by HPLC-MS revealed the presence of compounds belonging to phenolic acids (ferulic, syringic, vanillic, rosmarinic, chlorogenic, caffeic, coumaric, dihydroxybenzoic acids), flavonoids (eriodyctiol and cirsimaritin), and terpenes such as 6,11,12,14,16-Pentahydroxy-3,17diacetyl-8,11,13-abietatrien-7-one, 6,11,12,14,16-Pentahydroxy-3,17-diacetyl5,8,11,13-abietatetraen-7-one, and 3,6,12-Trihydroxy-2-acetyl-8,12-abietadien7,11,14-trione. The results show that both extracts have a cytotoxic and genotoxic effect against MCF-7 and A549 cancer cells, with a different degree of sensitivity. It was also shown that both extracts can induce apoptosis by altering the expression of apoptotic genes (Bax, Bcl-2, TP53, Fas, and TNFSF10), reducing mitochondrial membrane potential, increasing ROS levels, and increasing DNA damage. In addition, it has been shown that the tested extracts can alter blood coagulation parameters. Our results indicate that extracts from in vitro cultures of Plectranthus scutellarioides aerial parts and roots have promising therapeutic application, but further research is needed to better understand the mechanisms of their action in the in vitro model.

Calcimycin mediates apoptosis in breast and cervical cancer cell lines by inducing intracellular calcium levels in a P2RX4-dependent manner

BackgroundCalcimycin (A23187) is a polyether antibiotic and divalent cation ionophore, extracted from Streptomyces chartrecensis. With wide variety of antimicrobial activities, it also exhibits cytotoxicity of tumor cells. Calcimycin exhibit therapeutic potential against tumor cell growth; however, the molecular mechanism remains to be fully elucidated. Present study explores the mechanism of calcimycin-induced apoptosis cancer cell lines. MethodsApoptotic induction in a dose-dependent manner were recorded with MTT assays, Phase contrast imaging, wound healing assay, fluorescence imaging by DAPI and AO/EB staining and FACS using cell line model. Mitochondrial potential was analyzed by TMRM assay as Ca2+ signaling is well known to be influenced and synchronized by mitochondria also. ResultsCalcimycin induces apoptosis in dose dependent manner, also accompanied by increased intracellular calcium-level and expression of purinergic receptor-P2RX4, a ligand-gated ion channel. ConclusionCalcimycin tends to increase the intracellular calcium level, mRNA expression of ATP receptor P2RX4, and phosphorylation of p38. Blocking of either intracellular calcium by BAPTA-AM, P2RX4 expression by antagonist 5-BDBD, and phospho-p38 by SB203580, abrogated the apoptotic activity of calcimycin. General significanceTaken together, these results show that calcimycin induces apoptosis in P2RX4 and ATP mediated intracellular Ca2+ and p38 MAPK mediated pathway in both the cancer cell lines. This study explored a new mode of action for calcimycin in cancer that could be potentially employed in future studies for cancer therapeutic research. This study disentangles that the calcimycin-induced apoptotic cell death is P2RX4 and ATP involved, intracellular Ca2+ and p38 MAPK mediated pathway.

Quinoxalinone substituted pyrrolizine (4h)-induced dual inhibition of AKT and ERK instigates apoptosis in breast and colorectal cancer by modulating mitochondrial membrane potential

AKT and ERK 1/2 play a pivotal role in cancer cell survival, proliferation, migration, and angiogenesis. Therefore, AKT and ERK 1/2 are considered crucial targets for cancer intervention. In this study, we envisaged the role of AKT and ERK signaling in apoptosis regulation in presence of compound 4h, a novel synthetic derivative of quinoxalinone substituted spiropyrrolizines exhibiting substantial antiproliferative activity in various cancer cell lines. Structurally 4h is a spiropyrrolizine derivative. Molecular docking analysis revealed that compound 4h shows strong binding affinity with AKT-1 (−9.5 kcal/mol) and ERK2 (−9.0 kcal/mol) via binding at allosteric sites of AKT and active site of ERK2. The implications of 4h binding with these two survival kinases resulted in the obstruction for ATP binding, hence, hampering their phosphorylation dependent activation. We demonstrate that 4h mediated apoptotic induction via disruption in the mitochondrial membrane potential of MCF-7 and HCT-116 cells and 4h-mediated inhibition of survival pathways occurred in a wild type PTEN background and is diminished in PTEN−/− cells. In 4T1 mammary carcinoma model, 4h exhibited pronounced reduction in the tumor size and tumor volume at significantly low doses. Besides, 4h reached the highest plasma concentration of 5.8 μM within a period of 1 h in mice model intraperitoneally. Furthermore, 4h showed acceptable clearance with an adequate elimination half-life and satisfactory pharmacokinetic behaviour, thus proclaiming as a potential lead molecule against breast and colorectal cancer by specifically inhibiting simultaneously AKT and ERK1/2 kinases.

LOW LEVEL LASER THERAPY REDUCES ANTICANCER POTENTIAL OF COLLOIDAL SILVER THROUGH TRPV1 CHANNELS

Recently there are studies which particularly investigated efficiency of silver on neoplastic diseases. and many other diseases. Low level laser therapy(LLLT) has been shown to modulate biological processes and there are many studies that investigate the effect of LLLT, which is used in the treatment of cancers currently. Methods: Breast(MCF7) and colon(Caco 2) cells were cultured and cells were divided into eleven main groups. Cells were incubated with colloidal silver for 24 hrs. Colloidal silver and LLLT exposure separately and together performed on MCF7 and Caco 2 cell cultures. The effects of colloidal silver and LLLT were invastigated on all molecular pathways of apoptosis. Results: It was found that the levels of apoptosis in colloidal silver group were significantly increased in both cancer cells compared to control group. In both cancer cells, transient receptor protein vanilloid 1 (TRPV1) channel stimulator Cpsin administration resulted in significantly increased apoptosis levels compared to the control group, in colloidal silver + LLLT group the apopitosis level significantly reduced compared to colloidal silver-only group.Conclusions: It has been shown that colloidal silver significantly increases apoptosis in breast and colon cancer cells, however LLLT administration decreases apoptosis in both wavelength and suppressed apoptotic effect of colloidal silver significantly on these cells.

Abstract 516: Discovery and preclinical characterization of AMG 650, a first-in-class inhibitor of kinesin KIF18A motor protein with potent activity against chromosomally unstable cancers

Abstract Chromosomal instability (CIN) is a hallmark of human cancers and is caused by persistent errors in chromosome segregation during mitosis. Aggressive types of human cancer such as high-grade serous ovarian cancer and triple-negative breast cancer have elevated levels of CIN and frequently harbor TP53 gene alterations and are poorly served by current treatment options. These two CIN+ cancer types also share mutually exclusive genetic alterations in BRCA1 and CCNE1 cancer genes. KIF18A is a mitotic kinesin motor protein that localizes to the plus-end tips of kinetochore microtubule (MT) spindle fibers, where it regulates chromosome alignment during cell division. KIF18A is overexpressed in a subset of human cancers, and its elevated expression is associated with tumor aggressiveness. Recent reports provide compelling evidence that genetic ablation of KIF18A reduced the viability of CIN cancer cells (Marquis et al. Nature Com 2021, Quinton et al. Nature 2021, Cohen-Sharir et al. Nature 2021). Here, we report the discovery and preclinical characterization of AMG 650, a potent and selective inhibitor of KIF18A with a compelling anti-cancer profile distinct from other cell cycle and anti-mitotic drug targets. Structural insights gained by cryo-EM illustrate the unique binding mode of AMG 650 to an allosteric pocket at the interface of KIF18A motor α4 and α6 helices and α-tubulin. AMG 650 selectively inhibits KIF18A MT-ATPase motor activity (IC50 = 48 nM) and exhibits specificity against a panel of diverse motor proteins. In cells, AMG 650 is active at double-digit nM concentrations and phenocopies KIF18A genetic KD/KO dependencies across a panel of DNA-barcoded cancer cell lines. AMG 650 selectively activates the mitotic checkpoint resulting in multipolarity and apoptosis in breast and ovarian cancer cell lines enriched with CIN features. Notably, AMG 650 has minimal effects on proliferating human bone marrow mononuclear cells in culture at concentrations active on sensitive cancer cells (&amp;gt;100X window). In vivo, AMG 650 has low clearance, long half-life, and good oral bioavailability across preclinical species. In mice, oral administration of AMG 650 induces a dose-dependent pharmacodynamic response (pH3 mitotic marker) that is sustained for 24 hours in OVCAR-3 tumor model. Importantly, continuous once-daily dosing with AMG 650 shows robust anti-cancer activity with evidence of durable tumor regressions in a subset of human ovarian and breast CDX/PDX tumor models at well-tolerated doses. Lastly, the combination of AMG 650 with PARP inhibitor Olaparib enhances anti-cancer activity relative to single agent alone in BRCA1- and CCNE1-altered tumor models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via AMG 650, a first-in-class KIF18A inhibitor. Citation Format: Brian Belmontes, Jodi Moriguchi, Grace Chung, Jan Sun, Maria Stefania S. Ninniri, Kelly Hanestad, Kui Chen, John D. McCarter, Upendra P. Dahal, Sudipa Ghimire-Rijal, Yue Hao, Christopher P. Mohr, Xinchao Yu, Matthew G. Rees, Melissa Ronan, Jennifer Roth, Sheroy Minocherhomji, Jennifer R. Allen, Matthew P. Bourbeau, Paul E. Hughes, Nuria A Tamayo, Marc N. Payton. Discovery and preclinical characterization of AMG 650, a first-in-class inhibitor of kinesin KIF18A motor protein with potent activity against chromosomally unstable cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 516.

Design, synthesis and biological evaluation of pteridine-7(8H)-one derivatives as potent and selective CDK4/6 inhibitors

Cyclin-dependent kinases play an important role in the regulation of cell cycle and transcription. Selective CDK4/6 inhibitors have been demonstrated to be effective in the treatment of cancer. In this article, we described the design and synthesis of a series of pteridine-7(8H)-one derivatives as dual CDK4/6 inhibitors. Among them, the most promising compound L2 exhibited significant inhibitory activity against CDK4 and CDK6 with IC50 values of 16.7 nM and 30.5 nM respectively and showed excellent selectivity to CDK1/2/7/9. Moreover, compound L2 displayed potent antiproliferative activities at low digital micromolar range via inducing apoptosis in breast and colon cancer cells. In all, we developed a new series of pteridine-7(8H)-one derivatives which exhibited promising antitumor activities as selective CDK4/6 inhibitors.

Subtilisin from Bacillus amyloliquefaciens induces apoptosis in breast cancer cells through ubiquitin-proteasome-mediated tubulin degradation

To search for novel proteases from environmental isolates which can induce apoptosis in cancer cells, we have purified subtilisin from Bacillus amyloliquefaciens and studied its anti-cancer properties. Subtilisin induced apoptosis in colon (HT29) and breast (MCF7) cancer cells but showed no effect on mouse peritoneal macrophages and normal breast cells (MCF10A). Western blot analysis showed that Bax, Bcl-2 level remained unchanged but tubulin level decreased significantly. Subtilisin does not induce the intrinsic pathway of apoptosis, rather it induced tubulin degradation in MCF-7 cells, whereas in normal cells (MCF-10A) tubulin degradation was not observed. Subtilisin activates ubiquitination and proteasomal-mediated tubulin degradation which was completely restored in presence of proteasome inhibitor MG-132. We further observed PARKIN, one of the known E3-ligase, is overexpressed and interacts with tubulin in subtilisin treated cells. Knockdown of PARKIN effectively downregulates ubiquitination and inhibits degradation of tubulin. PARKIN activation and tubulin degradation lead to ER-stress which in turn activates caspase-7 and PARP cleavage, thus guiding the subtilisin treated cells towards apoptosis. To our knowledge this is the first report of subtilisin induced apoptosis in cancer cells by proteasomal degradation of tubulin.

Carnosic Acid Encapsulated in Albumin Nanoparticles Induces Apoptosis in Breast and Colorectal Cancer Cells.

Carnosic acid (CA) is a natural phenolic compound with several biomedical actions. This work was performed to study the use of CA-loaded polymeric nanoparticles to improve the antitumor activity of breast cancer cells (MCF-7) and colon cancer cells (Caco-2). CA was encapsulated in bovine serum albumin (BSA), chitosan (CH), and cellulose (CL) nanoparticles. The CA-loaded BSA nanoparticles (CA-BSA-NPs) revealed the most promising formula as it showed good loading capacity and the best release rate profile as the drug reached 80% after 10 h. The physicochemical characterization of the CA-BSA-NPs and empty carrier (BSA-NPs) was performed by the particle size distribution analysis, transmission electron microscopy (TEM), and zeta potential. The antitumor activity of the CA-BSA-NPs was evaluated by measuring cell viability, apoptosis rate, and gene expression of GCLC, COX-2, and BCL-2 in MCF-7 and Caco-2. The cytotoxicity assay (MTT) showed elevated antitumor activity of CA-BSA-NPs against MCF-7 and Caco-2 compared to free CA and BSA-NPs. Moreover, apoptosis test data showed an arrest of the Caco-2 cells at G2/M (10.84%) and the MCF-7 cells at G2/M (4.73%) in the CA-BSA-NPs treatment. RT-PCR-based gene expression analysis showed an upregulation of the GCLC gene and downregulation of the BCL-2 and COX-2 genes in cells treated with CA-BSA-NPs compared to untreated cells. In conclusion, CA-BSA-NPs has been introduced as a promising formula for treating breast and colorectal cancer.

Dynamical Analysis of a Boolean Network Model of the Oncogene Role of lncRNA ANRIL and lncRNA UFC1 in Non-Small Cell Lung Cancer.

Long non-coding RNA (lncRNA) such as ANRIL and UFC1 have been verified as oncogenic genes in non-small cell lung cancer (NSCLC). It is well known that the tumor suppressor microRNA-34a (miR-34a) is downregulated in NSCLC. Furthermore, miR-34a induces senescence and apoptosis in breast, glioma, cervical cancer including NSCLC by targeting Myc. Recent evidence suggests that these two lncRNAs act as a miR-34a sponge in corresponding cancers. However, the biological functions between these two non-coding RNAs (ncRNAs) have not yet been studied in NSCLC. Therefore, we present a Boolean model to analyze the gene regulation between these two ncRNAs in NSCLC. We compared our model to several experimental studies involving gain- or loss-of-function genes in NSCLC cells and achieved an excellent agreement. Additionally, we predict three positive circuits involving miR-34a/E2F1/ANRIL, miR-34a/E2F1/UFC1, and miR-34a/Myc/ANRIL. Our circuit- perturbation analysis shows that these circuits are important for regulating cell-fate decisions such as senescence and apoptosis. Thus, our Boolean network permits an explicit cell-fate mechanism associated with NSCLC. Therefore, our results support that ANRIL and/or UFC1 is an attractive target for drug development in tumor growth and aggressive proliferation of NSCLC, and that a valuable outcome can be achieved through the miRNA-34a/Myc pathway.

Ropinirole, a potential drug for systematic repositioning based on side effect profile for management and treatment of breast cancer

Drug repositioning offers two main advantages in drug discovery – the process is less tedious and less costly. In the past, many drugs like thalidomide and sildenafil were successfully repositioned but the process was entirely serendipitous. These days drug repositioning is widely accepted as an alternate method of drug discovery and the process is based on building a strong hypothesis guided by systematic computational and experimental methods. One of the methods used in drug repositioning is based on shared side effects by drugs of different pharmacological categories. This method rests on the principle that drugs that share side effects might also share common biological targets and therefore same pharmacological indications. Old drugs can be repositioned for new uses by identifying the shared side effects of existing drugs and by modulating their chemical structure if required. Breast cancer is the most common type of cancer in women and the second leading cause of death worldwide after lung cancer in both men and women. Letrozole, an aromatase inhibitor, is used in the treatment of advanced, recurrent and metastatic breast cancer in post-menopausal women. Identification of drugs that share side effects with letrozole might help us to identify a potential drug for repositioning in the treatment of breast cancer. Ropinirole, a dopaminergic agonist was found to share the maximum number of side effects with letrozole. Studies have proposed that dopaminergic agonists induce apoptosis in breast, colon, ovarian cancer cells and leukemia neuroblastoma. This is consistent with our hypothesis that ropinirole that shares the maximum number of side effects with letrozole might be effective in the management of breast cancer. This hypothesis was further validated by preliminary molecular docking and in-vitro cell-line studies.

MiR-449b-5p Inhibits Cell Proliferation and Migration of Breast Cancer via Targeting Flotillin-2

Background: MicroRNAs (miRNAs) act as a critical role in cancer pathogenesis, while the potential of miR-449b-5p in breast carcinoma remains to be fully inquired. Therefore, we purposed to probe the mechanism governing miR-449b-5p in breast cancer. Methods: Reverse transcription-PCR (RTPCR) was adopted to examine miR-449b-5p expression level in breast carcinoma. The functional experiments were implemented to estimate the role of miR-449b-5p in cell growth and migration. The interplay of miR-449b-5p with FLOT2 was validated with luciferase reporter assay. Results: miR-449b-5p level was markedly lessened in the tissue samples and cell lines of breast carcinoma. Overexpression of miR-449b-5p contributed to suppression of cell growth and migration whereas induced apoptosis in SKBr-3 and MCF-7 cells. Moreover, luciferase reporter experiment suggested that FLOT2 had a negative correlation with miR-449b-5p expression. Functionally, ectopic expression of FLOT2 reversed repressive effects of miR-449b-5p mimic on malignant behaviors of breast carcinoma cells. Conclusion: miR-449b-5p hindered cell proliferation, migration and facilitated cell apoptosis of breast carcinoma through targeting FLOT2. Our findings may offer a potent target for the therapy of breast carcinoma.

The Probiotic Bacteria Induce Apoptosis in Breast and Colon Cancer Cells: An Immunostimulatory Effect

Background: Uncontrolled cell proliferation and resistance to apoptosis are the main characteristics of cancer cells. Therefore, a substance with the capability to induce apoptosis in cancer cells could be known as an anti-cancer material. Probiotics are useful microorganisms that are crucial for the host’s health.Materials and Methods: In the present study, we evaluated the synergic effect of probiotic bacteria on the cytotoxic potency of cancer cells and apoptosis genes expression. Lactobacillus acidophilus and Bifidobacterium bifidum were cultured in MRS broth and then MTT test was performed on AGS, MCF-7, and peripheral mononuclear cells after treatment with the bacterial corpse. β-actin, Bcl2, Bax, TNF-α, and IFN-γ gene expression were evaluated in treated cell lines by real-time PCR method. Results: The result of cytotoxicity assay showed that bacterial corpse has higher cytotoxicity effects on cancer cells compared with normal cells. Results of gene expression demonstrated that Bcl2 and Bax gene expression significantly increased in cancer cells and TNF-α gene expression remarkably increased in normal cells as compared with the control group. Conclusion: Probiotic bacterial corpse can induce apoptosis in cancer cells. In normal cells, the immune system shifts responses toward Th1 and inflammatory cytokines.‎

Secondary Metabolites of Saussurea costus Leaf Extract Induce Apoptosis in Breast, Liver, and Colon Cancer Cells by Caspase-3-Dependent Intrinsic Pathway.

Background Apoptosis, a major form of programmed cell death, plays a vital role in regulating tissue development and maintenance of homeostasis in eukaryotes. Apoptosis can occur via a death receptor-dependent extrinsic or a mitochondrial-dependent intrinsic pathway and can be induced by various chemotherapeutic agents. In this study, the anticancer activity of Saussurea costus and its mode of intervention in human cancer cells of breast, colon, and liver were investigated. Results In this study, the bioactives of S. costus leaves were extensively extracted in five solvents of different polarity. The cytotoxicity and anticancer effect of the extracted secondary metabolites were investigated against breast (MCF-7), liver (HepG2), and colon (HCT116) cancer cell lines using a Sulphorhodamine B (SRB) assay. Secondary metabolites extracted using hexane, methanol, ethyl acetate, and chloroform had the highest cytotoxicity and thus the greatest anticancer effect on all the cancer cell lines tested (IC50; ranging from 0.25 to 2.5 μg/ml), while butanol was comparatively less active (IC50; ranging from 23.2 to 25.5 μg/ml). Further investigation using DNA flow cytometry and fluorescent microscopy revealed that the extract arrested the cells in the G1 phase of cell cycle and induced apoptosis. Furthermore, the elevated expression level of proapoptotic proteins and decreased expression level of antiapoptotic proteins confirmed that the intrinsic (mitochondrial) pathway was involved in mediating the apoptosis of cancer cells upon treatment with S. costus extract. These results altogether suggest that S. costus could be a potential anticancer agent. Conclusion These results suggest that the S. costus extract is the potential source of the secondary metabolites that could be used as anticancer agent to treat diverse cancers of breast, colon, and liver.

Micromeria fruticosa Induces Cell Cycle Arrest and Apoptosis in Breast and Colorectal Cancer Cells.

Micromeria fruticosa (L.) Druce subsp. serpyllifolia (Lamiaceae) has been used widely in folk medicine to alleviate various ailments such as abdominal pains, diarrhea, colds, eye infections, heart disorders and wounds. A few reports have confirmed different therapeutic potentialities of its extracts, including the anti-inflammatory, gastroprotective, analgesic, antiobesity and antidiabetic activities. This study aimed to investigate the mechanistic pathway of the antiproliferative activity of the ethanolic extract of M. fruticosa on two different cancer cell lines, namely human breast (mammary carcinoma F7 (MCF-7)) and human colorectal (human colon tumor cells (HCT-116)) cell lines. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide tetrazolium (MTT) assay, Annexin V-FITC/PI, caspases 8/9 and cell cycle analyses, qRT-PCR and Western blot were used to assess the effect of M. fruticosa on cytotoxicity, apoptosis, cell cycle, cell cycle-related genes and protein expression profiles in MCF-7 and HCT-116. The extract inhibits cell proliferation in a time- and dose-dependent manner. The half-maximal inhibitory concentration (IC50) for both cell lines was found to be 100 μg/mL. Apoptosis induction was confirmed by Annexin V-FITC/PI, that was related to caspases 8 and 9 activities induction. Furthermore, the cell cycle analysis revealed arrest at G2/M phase. The underlying mechanism involved in the G2/M arrest was found to be associated with the downregulation of CDK1, cyclin B1 and survivin that was confirmed by qRT-PCR and Western blotting.