Apoptosis In Lung Cancer Cells Research Articles

Beta-naphthoflavone and doxorubicin synergistically enhance apoptosis in human lung cancer cells by inducing doxorubicin accumulation, mitochondrial ROS generation, and JNK pathway signaling

Doxorubicin is one of the most effective chemotherapeutic agents available for treating various cancers, including lung cancer—the leading cause of cancer death in both men and women. However, its clinical application has been impeded by severe adverse effects, notably cardiotoxicity. Development of cellular resistance to doxorubicin is another major obstacle that must be overcome for broader application of the drug. In the present study, we examined the therapeutic potential of beta-naphthoflavone (BNF), a synthetic derivative of a naturally occurring flavonoid, in combination with doxorubicin for the treatment of lung cancer. Among our novel observations were that BNF enhances the efficacy of doxorubicin by inducing doxorubicin accumulation, mitochondrial ROS generation, and JNK pathway signaling in lung cancer cells. These combined effects were also evident in many other cancer cell types. BNF further exhibited synergistic induction of apoptosis in lung cancer cells when combined with several other cancer drugs, including irinotecan, cisplatin, and 5-fluorouracil. Our results suggest that BNF can be developed as a promising adjuvant agent for enhancing the efficacy of doxorubicin.

Mechanism of Puerariae Lobatae Radix against lung cancer by inhibiting histone demethylase LSD1

Histone lysine-specific demethylase 1(LSD1) has become a promising molecular target for lung cancer therapy. Upon the screening platform for LSD1 activity, some Chinese herbal extracts were screened for LSD1 activity inhibition, and the underlying mechanism was preliminarily investigated at both molecular and cellular levels. The results of LSD1 inhibition showed that Puerariae Lobatae Radix extract can effectively reduce LSD1 expression to elevate the expression of H3 K4 me2 and H3 K9 me2 substrates in H1975 and H1299 cells. Furthermore, Puerariae Lobatae Radix was evaluated for its anti-lung cancer activity. It had a potent inhibitory ability against the proliferation and colony formation of both H1975 and H1299 cells. Flow cytometry and DAPI staining assays indicated that Puerariae Lobatae Radix can induce the apoptosis of lung cancer cells. In addition, it can significantly suppress the migration and reverse the epithelial-mesenchymal transition(EMT) process of lung cancer cells by activating E-cadherin and suppressing the expression of N-cadherin, slug and vimentin. To sum up, Puerariae Lobatae Radix displayed a robust inhibitory activity against lung cancer, and the mechanism may be related to the down-regulation of LSD1 expression to induce the cell apoptosis and suppress the cell migration and EMT process. These findings will provide new insights into the action of Puerariae Lobatae Radix as an anti-lung cancer agent and offer new ideas for the study on the anti-cancer action of Chinese medicine based on the epigenetic modification.

BV6 enhances apoptosis in Lung cancer cells by ameliorating caspase expressions through attenuation of XIAP, cIAP-1, and cIAP-2 proteins

The present study aimed to investigate the inhibitory role of second mitochondria determined activator of caspases mimetic on inhibitor of apoptosis proteins (IAPs) and regulation of caspases in nonsmall cell lung cancer cell line. Dimethyl sulfoxide and 3-(4, 5-dimethyl thizol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay was done to determine the IC50 of BV6 using NCI-H23 cell line. The levels of mRNA of X-linked IAP (XIAP), cellular IAP (cIAP-1), cIAP-2, caspase-6, and caspase-7 in H23 cell line were evaluated by a quantitative real-time polymerase chain reaction, while their protein expressions were tested using western blotting. Two doses of BV6 dependently downregulated the expression of mRNA of XIAP (P = 0.002, P= 0.0003 vs. untreated), cIAP-1 (P = 0.05, P = 0.005 vs. untreated), and cIAP-2 (P = 0.001, P = 0.0002 vs. untreated), respectively, while the compound upregulated the mRNA expression of caspase-6 (P = 0.001, P < 0.0001 vs. untreated) and caspase-7 (P = 0.001, P = 0.0004 vs. untreated), respectively. Dose dependent of BV6 treatment significantly decreased the protein level of XIAP (P = 0.003, P = 0.007 vs. untreated), cIAP-1 (P = 0.02, P = 0.01 vs. untreated), and cIAP-2 (P = 0.008,P = 0.008 vs. untreated), respectively. However, the compound increased the protein level of caspase-6 and caspase-7 when compared to untreated control (P = 0.006,P = 0.001) and (P = 0.01, P = 0.001), respectively. The result showed that BV6 treatment reduced the level of mRNA of XIAP, cIAP-1, and cIAP-2 and increased the gene expression of caspase-6 and caspase-7 in NCI-H23 cell line. Therefore, the study revealed that BV6 could be used in future as additional therapeutics in lung cancer.

Novel mechanism of napabucasin, a naturally derived furanonaphthoquinone: apoptosis and autophagy induction in lung cancer cells through direct targeting on Akt/mTOR proteins

BackgroundAkt and mTOR are aberrantly activated in cancers and targeting these proteins are interesting for cancer drug discovery. Napabucasin (NB), a phytochemical compound, has been reported as potential anti-cancer agent, however, Akt and mTOR targeting mechanisms remain unclear. MethodApoptosis induction was investigated by Hoechst 33342/PI double staining and annexin V/PI staining with flowcytometry. Autophagy was evaluated by monodansylcadaverine staining and Western blot analysis. Binding affinity of NB and essential signaling proteins (PI3K, Akt, and mTOR) was investigated using molecular docking and confirmed by Western blot analysis.ResultA structure modification from changing methyl moiety of acetyl group of NB to hydroxyl moiety of carboxyl group of NB derivative (napabucasin-acid or NB-acid) greatly affected the compound activities. NB showed more potent anti-cancer activity. NB reduced cell viability with an approximately 20 times lower IC50 and inhibited the colony formation capacity much more than NB-acid treated cells. NB induced cell apoptosis, which was accompanied by decrease Bcl‑2 and Mcl-1 and clevage of PARP, while NB-acid show lesser effect on Mcl-1. NB was found to strongly induce autophagy indicated by acidic vesicle staining and the LC3B conversion. Interestingly, computational molecular docking analysis further demonstrated that NB directly bound to Akt and mTOR (complex 1 and 2) proteins at their critical sites indicating that NB targets the upstream regulators of apoptosis and autophagy. The docking results were confirmed by decrease of p-Akt/Akt, p-mTOR/mTOR, and c-Myc a downstream target of Akt protein levels.ConclusionResults show for the first time that NB exerts an anti-cancer activity through the direct interaction to Akt and mTOR proteins. The methyl moiety of acetyl group of NB is required for its potent anti-cancer activities. These data encourage further development of NB compounds for Akt and mTOR driven cancers.

Lung Cancer Cell Apoptosis Induced by Two New Trinuclear Cluster-Based Coordination Polymers

Lung Cancer Cell Apoptosis Induced by Two New Trinuclear Cluster-Based Coordination Polymers

The reversion of DNA methylation-induced miRNA silence via biomimetic nanoparticles-mediated gene delivery for efficient lung adenocarcinoma therapy

BackgroundLung cancer is one of the fatal cancers worldwide, and over 60% of patients are lung adenocarcinoma (LUAD). Our clinical data demonstrated that DNA methylation of the promoter region of miR-126-3p was upregulated, which led to the decreased expression of miR-126-3p in 67 cases of lung cancer tissues, implying that miR-126-3p acted as a tumor suppressor. Transduction of miR-126-3p is a potential therapeutic strategy for treating LUAD, yet the physiological environment and properties of miRNA challenge current transduction approaches.MethodsWe evaluated the expression of miR-126-3p in 67 pairs of lung cancer tissues and the corresponding adjacent non-tumorous tissues by Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The relationship between the overall survival of lung cancer patients and miR-126-3p was analyzed by the Cancer Genome Atlas cohort database (Oncolnc, http://www.oncolnc.org). We analyzed DNA methylation Methylation-specific PCR (MSP) analysis. To determine whether ADAM9 is the direct target of miR-126-3p, we performed the 3′-UTR luciferase reporter assay. The protein levels in the cells or tissues were evaluated with western blotting (WB) analysis. The biodistribution of nanoparticles were monitored by in vivo tracking system.ResultsWe describe the development of novel stealth and matrix metalloproteinase 2 (MMP2)-activated biomimetic nanoparticles, which are constructed using MMP2-responsive peptides to bind the miR-126-3p (known as MAIN), and further camouflaged with red blood cell (RBC) membranes (hence named REMAIN). REMAIN was able to effectively transduce miRNA into lung cancer cells and release them via MMP2 responsiveness. Additionally, REMAIN possessed the advantages of the natural RBC membrane, including extended circulation time, lower toxicity, better biocompatibility, and immune escape. Moreover, in vitro and in vivo results demonstrated that REMAIN effectively induced apoptosis of lung cancer cells and inhibited LUAD development and progression by targeting ADAM9.ConclusionThe novel style of stealth and MMP2-activated biomimetic nanoparticles show great potential in miRNA delivery.

Rapid assembly of 1,3-indanedione-based spirocyclic tetrahydroquinolines for inducing human lung cancer cell apoptosis

The rapid collection of a library of biologically relevant molecules is essential in new drug discovery. Here we show a variety of bioactive 1,3-indanedione-based spirocyclic tetrahydroquinolines that have been concisely and efficiently constructed under the guidance of biology-oriented synthesis (BIOS). Using Pd(PPh3)4 as a catalyst, various 2-arylidene-1,3-indanediones can react with vinyl benzoxazinanones under the mild condition to afford a new class of spirocyclic tetrahydroquinolines in moderate to excellent yields (45%–99%) with high stereocontrol (>95:5 diastereoselectivity). Their structures were unambiguously confirmed by X-ray single crystal analysis. The biological evaluation revealed that two of the 1,3-indanedione-based spirocyclic tetrahydroquinolines show remarkable apoptosis-inducing activities over A549 human lung cancer cells, exceeding that of cisplatin. The antitur activities were triggered by reactive oxygen species, commonly overproduced in cancer cells. The clinical demand for antitumor chemotherapy for lung cancer has encouraged an all-out search for analogues with lower toxcity, improved therapeutic index and increased activity.

In vitro and in vivo anti-lung cancer activity of emodin: A RNA-seq transcriptome analysis.

Emodin is a natural anthraquinone extract of Chinese medicinal herbs. Several studies demonstrated the antitumor activity of this extract, particularly for lung cancer. However, the mode of action of emodin remains obscure. In this study we evaluated in vitro and in vivo anti-lung cancer properties of emodin in human lung adenocarcinomas and the underlying molecular mechanism involved. Our results demonstrated emodin caused a significant inhibition of cell viability and induced apoptosis in lung cancer cells to a level that is relative to that of normal epithelial cells. Furthermore, RNA-seq transcriptome analysis revealed 65 common genes(>2-fold change) with a significant expression in A549, and H1650 cells under emodin treatment. In vitro qRT-PCR results confirmed that 4 genes (ATP6V0D2, C11orf96, TIPARP, and CDKN1A) were up-regulated, and 9 genes (TNFSF10, IFIT1, EGLN3, RCOR2, ARRB1, FLVCR2, BAIAP2-DT, FAM111B, and TGFB2) were down-regulated in A549 and H1650 adenocarcinoma cell lines. The in vivo experiment demonstrated emodin could significantly decrease tumor volume and tumor weight of mice compared with the control group. However, emodin treatment has no obvious effect on body weight of mice. Moreover, in vivo qRT-PCR results revealed that 3 genes (ATP6V0D2, C11orf96, and TIPARP) were up-regulated, and 6 genes (TNFSF10, IFIT1, EGLN3, BAIAP2-DT, FAM111B, and TGFB2) were down-regulated in tumor tissues compared with the control group. These findings suggested that emodin could help treat lung cancer and has a potential for further investigations as an anti-lung cancer drug.

EIF3C Promotes Lung Cancer Tumorigenesis by Regulating the APP/HSPA1A/LMNB1 Axis.

Objective This study was designed to explore the role and mechanism of eukaryotic initiation factor 3C (EIF3C) in the proliferation and apoptosis of lung cancer cells. Methods EIF3C expression in clinic lung cancer tissues was detected by immunohistochemistry assay. Cell transfection with lentivirus EIF3C short hairpin RNA (shRNA) was performed with Lipofectamine 2000. Cell proliferation was evaluated by Celigo and MTT assays. Caspase-3/7 activity was assessed using caspase-3/7 assay kit for cell apoptosis detection. The apoptosis rate of lung cancer cells was assessed by flow cytometry. A transplanted tumor nude-mouse model was established to clarify the role of EIF3C in lung cancer. The potential mechanism of EIF3C was explored by mRNA microarray analysis. Among the top 30 up- and downregulated mRNAs selected for RT-qPCR, 5 were chosen for western blot analysis. Results EIF3C was abnormally overexpressed in lung cancer cell lines and tissues. Silencing EIF3C suppressed the proliferation and promoted the apoptosis of lung cancer cells. In vivo experiments using transplanted tumor nude-mouse model suggested that EIF3C promoted lung cancer tumorigenesis. Further, mRNA microarray analyses identified 189 upregulated and 83 downregulated differentially expressed mRNA between the KD and negative control groups. After validation by RT-qPCR and western blot, three downstream genes (APP, HSPA1A, and LMNB1) were confirmed. Conclusion EIF3C overexpression may facilitate the proliferation and hamper the apoptosis of lung cancer cells by regulating the APP/HSPA1A/LMNB1 axis.

Polyphyllin II induced apoptosis of NSCLC cells by inhibiting autophagy through the mTOR pathway

Context Polyphyllin II (PPII) is a steroidal saponin isolated from Rhizoma Paridis. It exhibits significant antitumor activity such as anti-proliferation and pro-apoptosis in lung cancer. Objective To explore whether PPII induce autophagy and the relationship between autophagy and apoptosis in non-small cell lung cancer (NSCLC) cells. Materials and methods The effects of PPII (0, 1, 5, and 10 μM) were elucidated by CCK8 assay, colony formation test, TUNEL staining, MDC method, and mRFP-GFP-LC3 lentivirus transfection in A549 and H1299 cells for 24 h. DMSO-treated cells were selected as control. The protein expression of autophagy (LC3-II, p62), apoptosis (Bcl-2, Bax, caspase-3) and p-mTOR was detected by Western blotting. We explored the relationship between autophagy and apoptosis by autophagy inhibitor CQ (10 μM) and 3-MA (5 mM). Results PPII (0, 1, 5, and 10 μM) inhibited the proliferation and induced apoptosis. The IC50 values of A549 and H1299 cells were 8.26 ± 0.03 and 2.86 ± 0.83 μM. We found that PPII could induce autophagy. PPII promoted the formation of autophagosome, increased the expression of LC3-II/LC3-I (p < 0.05), while decreased p62 and p-mTOR (p < 0.05). Additionally, the co-treatment with autophagy inhibitors promoted the protein expression of c-caspase-3 and rate of Bax/Bcl-2 (p < 0.05), compared with PPII-only treatment group. Therefore, our results indicated that PPII-induced autophagy may be a mechanism to promote cell survival, although it can also induce apoptosis. Conclusions PPII-induced apoptosis exerts its anticancer activity by inhibiting autophagy, which will hopefully provide a prospective compound for NSCLC treatment.

Anti-migratory effect of curcumin on A-549 lung cancer cells via epigenetic reprogramming of RECK/ matrix metalloproteinase axis.

The aim of this study was to investigate theeffects of curcumin on the viability, migration, andapoptosis of A549 lung cancer cells. Furthermore, RECK/MMPs axis as a probable regulator of cancer cell migration was assessed. In this study, effect of curcumin on viability changes, cell migration, and percentage of apoptosis of A549 non-small cell lung carcinoma was examined. The methylation status of RECK gene was investigated using MS-HRM technique. Moreover, expression changes of genes involved in apoptosis and migration (including CASP3, CASP8, CASP9, BAX, BCL2, MMP9, MMP2, and RECK) were investigated by quantitative Real-Time PCR. The results of MTT assay showed that the cytotoxic effect of curcumin was in a dose dependent manner. Flow cytometry results demonstrated a significant increase in thepercentage of apoptotic cells in curcumin treated group. In addition, curcumin inhibited migration rate in lung cancer cells. qRT-PCR revealed that expression of the candidate genes was in line with suppressed growth andmigration. This could be due to, decreased methylation ofthe RECK gene promoter after curcumin treatment. Curcumin inhibited lung cancer cells through various molecular pathways. RECK/MMPs axis as a regulator of cancer cell migration was modulated after curcumin treatment and invasion of lung cancer cells was decreased.

Impaired Cdc20 signaling promotes senescence in normal cells and apoptosis in non–small cell lung cancer cells

Cellular senescence is a form of irreversible growth arrest that cancer cells evade. The cell division cycle protein 20 homolog (Cdc20) is a positive regulator of cell division, but how its dysregulation may relate to senescence is unclear. Here, we find that Cdc20 mRNA and protein expression are downregulated in stress-induced premature senescent lung fibroblasts in a p53-dependent manner. Either Cdc20 downregulation or inhibition of anaphase-promoting complex/cyclosome (APC/C) is sufficient to induce premature senescence in lung fibroblasts, while APC/C activation inhibits stress-induced premature senescence. Mechanistically, we show both Cdc20 downregulation and APC/C inhibition induce premature senescence through glycogen synthase kinase (GSK)-3β–mediated phosphorylation and downregulation of securin expression. Interestingly, we determined Cdc20 expression is upregulated in human lung adenocarcinoma. We find that downregulation of Cdc20 in non–small cell lung cancer (NSCLC) cells is sufficient to inhibit cell proliferation and growth in soft agar and to promote apoptosis, but not senescence, in a manner dependent on downregulation of securin following GSK-3β-mediated securin phosphorylation. Similarly, we demonstrate securin expression is downregulated and cell viability is inhibited in NSCLC cells following inhibition of APC/C. Furthermore, we show chemotherapeutic drugs downregulate both Cdc20 and securin protein expression in NSCLC cells. Either Cdc20 downregulation by siRNA or APC/C inhibition sensitize, while securin overexpression inhibits, chemotherapeutic drug-induced NSCLC cell death. Together, our findings provide evidence that Cdc20/APC/C/securin-dependent signaling is a key regulator of cell survival, and its disruption promotes premature senescence in normal lung cells and induces apoptosis in lung cancer cells that have bypassed the senescence barrier.

Brusatol Inhibits Proliferation, Migration, and Invasion of Nonsmall Cell Lung Cancer PC-9 Cells

Objective: The purpose of this study was to investigate the inhibitory effect of brusatol, a nigakilactone extracted from Brucea javanica, on lung cancer for development of therapeutic drugs. We explored the effects of brusatol on the proliferation, migration, and invasion of lung cancer PC-9 cells in vitro and analyzed the mechanisms involved. Materials and Methods: MTT assay was used to determine the effect of brusatol on the proliferative capacity of PC-9 and H1975 cells in vitro. The half-maximal inhibitory concentrations (IC50) were calculated and used as a reference for subsequent experiments. Variations in the number and size of tumor cell clusters were monitored by the colony formation assay as evidence for the effect of brusatol on cell proliferation. The effect of brusatol on the migration and invasion of PC-9 cells was evaluated using wound healing and transwell assays, respectively. Apoptosis in lung cancer cells was detected using the Annexin V-FITC/propidium iodide assay. The correlated anticancer mechanism was detected using Western blotting. Results: The IC50 values of brusatol acting on PC-9 and H1975 cells were 1.58 ± 0.30 mM and 31.34 ± 2.72 mM, respectively, according to the MTT experiment. In addition, brusatol suppressed PC-9 cell proliferation, migration, and invasion, as well as induced apoptosis, which may be related to the downregulation of epidermal growth factor receptor (EGFR), β-catenin, Akt, and STAT3 expression. Conclusions: Brusatol showed potent anticancer activity against lung cancer PC-9 cells, inhibiting the proliferative capacity and metastatic potential of PC-9 cells. Its anticancer effect may be related to the downregulation of EGFR, β-catenin, Akt, and STAT3.

Modulatory role of BV6 and chloroquine on the regulation of apoptosis and autophagy in non-small cell lung cancer cells.

Non-small cell lung cancer (NSCLC) is one of the aggressive tumors mostly diagnosed in the advanced stage. Therapeutic failure and drug resistance pose a major problem in NSCLC treatment primarily due to alterations in autophagy and loss of apoptosis. Therefore, the present study aimed to investigate the importance of the second mitochondria-derived activator of caspase mimetic BV6 and autophagy inhibitor chloroquine (CQ) on the regulation of apoptosis and autophagy, respectively. Study was conducted on NCI-H23 and NCI-H522 cell lines to evaluate the effect of BV6 and CQ on the transcription and translation level of LC3-II, caspase-3, and caspase-9 genes by quantitative real-time-polymerase chain reaction and western blotting techniques. In NCI-H23 cell line, BV6 and CQ treatments showed increased mRNA and protein expression of caspase-3, and caspase-9 compared to its untreated counterpart. BV6 and CQ treatments also caused downregulation of LC3-II protein expression compared to its counterpart. In NCI-H522 cell line, BV6 treatment showed a significantly increased expression of caspase-3 and caspase-9 mRNA and protein expression levels whereas BV6 treatment downregulated the expression level of LC3-II protein. A similar pattern was also observed in CQ treatment when compared with the respective controls. Both BV6 and CQ modulated in vitro expression of caspases and LC3-II which have critical regulatory roles in apoptosis and autophagy, respectively. Our findings suggest that BV6 and CQ could be promising candidates in NSCLC treatment and there is a need to explore them in vivo and in clinical applications.

Circ_0001955 promotes the progression of non-small cell lung cancer via miR-769-5p/EGFR axis

ABSTRACT To elaborate on the role of circular RNA 0001955 (circ_0001955) on the proliferation and apoptosis of non-small cell lung cancer (NSCLC) cells and its underlying mechanism. Circ_0001955 expression in NSCLC was screened out through bioinformatics analysis based on GEO database. Circ_0001955, microRNA-769-5p (miR-769-5p), and epidermal growth factor receptor (EGFR) expression in NSCLC tissues and cell lines was examined using quantitative real-time PCR (qRT-PCR) and Western blot. Cell proliferation and apoptosis were examined using the CCK-8 method, BrdU experiment and flow cytometry analysis, respectively. Bioinformatics prediction, dual-luciferase reporter gene experiment and RNA immunoprecipitation (RIP) experiments were applied to validate the targeting relationship between miR-769-5p and circ_0001955 and the 3’ UTR of EGFR. Pearson’s correlation analysis was employed to validate the correlations among them. Circ_0001955 expression was up-regulated in NSCLC tissues and cell lines, and its overexpression was strongly associated with increased tumor TNM stage and lymph node metastasis. Circ_0001955 overexpression enhanced the proliferation and restrained the apoptosis in NSCLC cells, whereas knocking down circ_0001955 exerted the opposite effects. Circ_0001955 directly targeted miR-769-5p and negatively regulated its expression. EGFR, a target gene of miR-769-5p, could be indirectly and positively regulated by circ_0001955. Correlation analysis indicated that circ_0001955 was negatively correlated with miR-769-5p expression, while circ_0001955 was positively correlated with EGFR expression. Circ_0001955 facilitates the proliferation and represses the apoptosis of NSCLC cells by modulating miR-769-5p/EGFR axis.

Delivery of Therapeutic miR-148b Mimic via Poly(β Amino Ester) Polyplexes for Post-transcriptional Gene Regulation and Apoptosis of A549 Cells.

In this study, we utilized selectively modified, biodegradable polymer-based polyplexes to deliver custom, exogenous miR-148b mimics to induce apoptosis in human lung cancer (A549) cells. The gene regulatory effects of the payload miRNA mimics (miR-148b-3p) were first evaluated through bioinformatic analyses to uncover specific gene targets involved in critical carcinogenic pathways. Hyperbranched poly(β amino ester) polyplexes (hPBAE) loaded with custom miR-148b mimics were then developed for targeted therapy. When evaluated in vitro, these hPBAE-based polyplexes sustained high intracellular uptake, low cytotoxicity, and efficient escape from endosomes to deliver functionally intact miRNA mimics to the cytosol. High-resolution confocal microscopy revealed successful intracellular uptake, cell viability was assessed through qualitative fluorescence microscopy and fluorescence-based DNA quantification, and successful cytosolic delivery of intact miRNA mimics was evaluated using real-time polymerase chain reaction (RT-PCR) to demonstrate target gene knockdown. The hPBAE-miRNA mimic polyplexes were shown to induce apoptosis among A549 cells through direct modulation of intracellular protein expression, targeting multiple potential carcinogenic pathways at the gene level. These results indicated that spatially controlled miR-148b mimic delivery can promote efficient cancer cell death in vitro and may lead to an enhanced therapeutic design for in vivo application.

Quick Release of Hydrogen Peroxide from Carbamide Peroxide Promotes Apoptosis of A549 Lung Cancer Cells

AbstractLung cancer is one of the malignant tumors with the leading morbidity and mortality worldwide. H2O2 is an important oxidant, and lethal to tumor cells. The present study aimed to explore new higher‐H2O2‐content and faster‐H2O2‐release rate carbamide peroxide (CP) compounds for treatment of lung cancer. The CP added with benzoic acid termed CP−B was applied in the research. Fenton reaction was used to determine the content and rate of H2O2 release by degrading organic small molecule dyes. The results showed that CP−B could be decolorized 200 mg/L RhB solution within 60 s. The phenotype was analyzed by vitro experiment the effects of the CP compound on A549 lung cancer cell line. The results showed that CP−B had a significant effect on pro‐apoptosis, anti‐proliferation and anti‐migration of A549 cells. Using RNA seq, it was found that CP−B might up‐regulate the INS‐IGF2 gene and it was closely related to the PI3 K/AKT signaling pathway. Finally, in vivo experiments indicated that CP−B has extremely low side effects and potentially tumor treatment capabilities.

MiR-199a: A Tumor Suppressor with Noncoding RNA Network and Therapeutic Candidate in Lung Cancer.

Lung cancer is the leading cause of cancer death worldwide. miR-199a, which has two mature molecules: miR-199a-3p and miR-199a-5p, plays an important biological role in the genesis and development of tumors. We collected recent research results on lung cancer and miR-199a from Google Scholar and PubMed databases. The biological functions of miR-199a in lung cancer are reviewed in detail, and its potential roles in lung cancer diagnosis and treatment are discussed. With miR-199a as the core point and a divergence outward, the interplay between miR-199a and other ncRNAs is reviewed, and a regulatory network covering various cancers is depicted, which can help us to better understand the mechanism of cancer occurrence and provide a means for developing novel therapeutic strategies. In addition, the current methods of diagnosis and treatment of lung cancer are reviewed. Finally, a conclusion was drawn: miR-199a inhibits the development of lung cancer, especially by inhibiting the proliferation, infiltration, and migration of lung cancer cells, inhibiting tumor angiogenesis, increasing the apoptosis of lung cancer cells, and affecting the drug resistance of lung cancer cells. This review aims to provide new insights into lung cancer therapy and prevention.

Gitogenin suppresses lung cancer progression by inducing apoptosis and autophagy initiation through the activation of AMPK signaling

Lung cancer is a leading cause of tumor-associated death worldwide. Autophagy plays a key role in regulating lung cancer progression, and is a promising option for lung cancer treatment. Saponins are a group of naturally occurring plant glycosides, characterized by their strong foam-forming properties in aqueous solution, and exert various biological properties, such as anti-inflammation and anti-cancer. In the present study, we for the first time explored the effects of gitogenin (GIT), an important saponin derived from Tribulus longipetalus, on lung cancer progression both in vitro and in vivo. We found that GIT markedly reduced the proliferation and induced apoptosis in lung cancer cells through increasing the cleavage of Caspase-3 and poly (ADP-ribose) polymerases (PARPs). In addition, GIT-incubated lung cancer cells exhibited clear accumulation of autophagosome, which was essential for GIT-suppressed lung cancer. Mechanistically, GIT-induced autophagy initiation was mainly through activating AMP-activated protein kinase (AMPK) and blocking protein kinase B (AKT) signaling pathways, respectively. Moreover, the autophagic flux was disrupted in GIT-treated lung cancer cells, contributing to the accumulation of impaired autophagolysosomes. Importantly, we found that suppressing autophagy initiation could abolish GIT-induced cell death; however, autophagosomes accumulation sensitized lung cancer cells to cell death upon GIT treatment. More in vitro experiments showed that GIT led to reactive oxygen species (ROS) production in lung cancer cells, which was also involved in the modulation of apoptosis. The in vivo findings confirmed the effects of GIT against lung cancer progression with undetectable toxicity to organs. In conclusion, we provided new insights into the treatment of lung cancer, and GIT might be an effective strategy for future clinical application.

Cold atmospheric plasma induces apoptosis in human colon and lung cancer cells through modulating mitochondrial pathway.

Cold atmospheric plasma (CAP) is an emerging and promising oncotherapy with considerable potential and advantages that traditional treatment modalities lack. The objective of this study was to investigate the effect and mechanism of plasma-inhibited proliferation and plasma-induced apoptosis on human lung cancer and colon cancer cells in vitro and in vivo. Piezobrush® PZ2, a handheld CAP unit based on the piezoelectric direct discharge technology, was used to generate and deliver non-thermal plasma. Firstly, CAPPZ2 treatment inhibited the proliferation of HT29 colorectal cancer cells and A549 lung cancer cells using CCK8 assay, caused morphological changes at the cellular and subcellular levels using transmission electron microscopy, and suppressed both types of tumor cell migration and invasion using the Transwell migration and Matrigel invasion assay. Secondly, we confirmed plasma-induced apoptosis in the HT29 and A549 cells using the AO/EB staining coupled with flow cytometry, and verified the production of apoptosis-related proteins, such as cytochrome c, PARP, cleaved caspase-3 and caspase-9, Bcl-2 and Bax, using western blotting. Finally, the aforementioned in vitro results were tested in vivo using cell-derived xenograft mouse models, and the anticancer effect was confirmed and attributed to CAP-mediated apoptosis. The immunohistochemical analysis revealed that the expression of cleaved caspase-9, caspase-3, PARP and Bax were upregulated whereas that of Bcl-2 downregulated after CAP treatment. These findings collectively suggest that the activation of the mitochondrial pathway is involved during CAPPZ2-induced apoptosis of human colon and lung cancer cells in vitro and in vivo.