Knocking down USP39 Inhibits the Growth and Metastasis of Non-Small-Cell Lung Cancer Cells through Activating the p53 Pathway

Ubiquitin-specific protease 39 (USP39), a member of the deubiquitinating enzyme family, has been reported to participate in cytokinesis and metastasis. Previous studies determined that USP39 functions as an oncogenic factor in various types of cancer. Here, we reported that USP39 is frequently overexpressed in human lung cancer tissues and non-small-cell lung cancer (NSCLC) cell lines. USP39 knockdown inhibited the proliferation and colony formation of A549 and HCC827 cells and decreased tumorigenic potential in nude mice. Specifically, knocking down USP39 resulted in cell cycle arrest at G2/M and subsequent apoptosis through the activation of the p53 pathway, including upregulation of p21, cleaved-cas3, cleaved-cas9 and downregulation of CDC2 and CycinB1. Moreover, USP39 knockdown significantly inhibited migration and invasion of A549 and HCC827 cells, also via activation of the p53 pathway, and downregulation of MMP2 and MMP9. Importantly, we verified these results in metastasis models in vivo. Collectively, these results not only establish that USP39 functions as an oncogene in lung cancer, but reveal that USP39 has an essential role in regulating cell proliferation and metastasis via activation of the p53 pathway.     

Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1

The Warburg effect is important for cancer cell proliferation. This phenomenon can be flexible by interaction between glycolysis and mitochondrial oxidation for energy production. We aimed to investigate the anticancer effects of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate (DCA) and the mitochondrial respiratory complex I inhibitor metformin in liver cancer cells. The anticancer effect of DCA and/or metformin on HepG2, PLC/PRF5 human liver cancer cell lines, MH-134 murine hepatoma cell lines, and primary normal hepatocytes using MTT assay. Inhibition of lactate/ATP production and intracellular reactive oxygen species generation by DCA and metformin was investigated. Inhibition of PI3K/Akt/mTOR complex I was evaluated to see whether it occurred through AMPK signaling. Anticancer effects of a combination treatment of DCA and metformin were evaluated in HCC murine model. The results showed that metformin and DCA effectively induced apoptosis in liver cancer cells. A combination treatment of metformin and DCA did not affect viability of primary normal hepatocytes. Metformin upregulated glycolysis in liver cancer cells, thereby increasing sensitivity to the DCA treatment. Metformin and DCA inhibited mTOR complex I signaling through upregulated AMPK-independent REDD1. In addition, metformin and DCA increased reactive oxygen species levels in liver cancer cells, which induced apoptosis. A combination treatment of metformin and DCA significantly suppressed the tumor growth of liver cancer cells using in vivo xenograft model. Taken together, the combined treatment of metformin and DCA suppressed the growth of liver cancer cells. This strategy may be effective for patients with advanced liver cancer.     

20(S)-原人参二醇抑制小细胞肺癌A549细胞增殖的研究

采用台盼蓝和MTT法测定20（S）-原人参二醇（Ppd）对肺癌A549细胞增殖的抑制作用,Hochest 33258染色和DNA Ladder方法观察Ppd对小细胞肺癌A549细胞凋亡及周期的影响。结果表明,Ppd对肺癌A549细胞具有明显的抑制作用并有剂量时间依赖关系,可明显降低肺癌A549细胞的存活率和活性（IC50为20.7μmol/L）;染色后肺癌A549细胞核出现典型的凋亡形态学变化,与DNA Ladder电泳条带弥散情况一致。因此,Ppd对肺癌A549细胞的增殖有明显的抑制作用。     

吴茱萸碱对人结肠癌lovo细胞生长的抑制作用

目的探讨吴茱萸碱(Evodiamine,Evo)在体内外对人结肠癌lovo细胞生长的抑制作用及其机制。方法采用MTT法检测Evo对人结肠癌lovo细胞、人乳腺癌MDA-MB-231细胞以及人肺癌A549细胞生长的影响;流式细胞术分析Evo对lovo细胞细胞周期和细胞凋亡的影响;采用Evo治疗lovo细胞荷瘤裸鼠,并绘制肿瘤生长曲线;Westernblot法检测Evo对lovo细胞和肿瘤组织中Bcl-2及procaspase-3表达的影响。结果 Evo能抑制lovo细胞生长(P<0.01),促进MDA-MB-231细胞增殖(P<0.01),对A549细胞无明显作用(P>0.05);可将lovo细胞阻滞于S期(P<0.01),并呈时间依赖性诱导其凋亡(P<0.01);能抑制lovo细胞荷瘤裸鼠肿瘤生长(P<0.05);Westernblot检测结果显示,Evo在体内外均可降低lovo细胞Bcl-2及procas-pase-3的表达。结论 Evo可通过抑制Bcl-2表达,激活caspase-3,诱导凋亡,从而抑制lovo细胞的生长。     

Protective Effect of Caffeic Acid on Paclitaxel Induced Anti-Proliferation and Apoptosis of Lung Cancer Cells Involves NF-κB Pathway

Caffeic acid (CA), a natural phenolic compound, is abundant in medicinal plants. CA possesses multiple biological effects such as anti-bacterial and anti-cancer growth. CA was also reported to induce fore stomach and kidney tumors in a mouse model. Here we used two human lung cancer cell lines, A549 and H1299, to clarify the role of CA in cancer cell proliferation. The growth assay showed that CA moderately promoted the proliferation of the lung cancer cells. Furthermore, pre-treatment of CA rescues the proliferation inhibition induced by a sub-IC(50) dose of paclitaxel (PTX), an anticancer drug. Western blot showed that CA up-regulated the pro-survival proteins survivin and Bcl-2, the down-stream targets of NF-κB. This is consistent with the observation that CA induced nuclear translocation of NF-κB p65. Our study suggested that the pro-survival effect of CA on PTX-treated lung cancer cells is mediated through a NF-κB signaling pathway. This may provide mechanistic insights into the chemoresistance of cancer calls.     

The Anti-Cancer Effects of a Zotarolimus and 5-Fluorouracil Combination Treatment on A549 Cell-Derived Tumors in BALB/c Nude Mice

Zotarolimus is a semi-synthetic derivative of rapamycin and a novel immunosuppressive agent used to prevent graft rejection. The pharmacological pathway of zotarolimus restricts the kinase activity of the mammalian target of rapamycin (mTOR), which potentially leads to reductions in cell division, cell growth, cell proliferation, and inflammation. These pathways have a critical influence on tumorigenesis. This study aims to examine the anti-tumor effect of zotarolimus or zotarolimus combined with 5-fluorouracil (5-FU) on A549 human lung adenocarcinoma cell line implanted in BALB/c nude mice by estimating tumor growth, apoptosis expression, inflammation, and metastasis. We established A549 xenografts in nude mice, following which we randomly divided the mice into four groups: control, 5-FU (100 mg/kg/week), zotarolimus (2 mg/kg/day), and zotarolimus combined with 5-FU. Compared the results with those for control mice, we found that mice treated with zotarolimus or zotarolimus combined with 5-FU retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; decreased inflammation cytokines levels (e.g., IL-1β, TNF-α, and IL-6); reduced inflammation-related factors such as cyclooxygenase-2 (COX-2) protein and nuclear factor-κB (NF-κB) mRNA; enhanced anti-inflammation-related factors including IL-10 and inhibitor of NF-κB kinase α (IκBα) mRNA; and inhibited metastasis-related factors such as transforming growth factor β (TGF-β), CD44, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). Notably, mice treated with zotarolimus combined with 5-FU had significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with the groups of mice treated with 5-FU or zotarolimus alone. The in vivo study confirmed that zotarolimus or zotarolimus combined with 5-FU could retard lung adenocarcinoma growth and inhibit tumorigenesis. Zotarolimus and 5-FU were found to have an obvious synergistic tumor-inhibiting effect on lung adenocarcinoma. Therefore, both zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents for treatment of human lung adenocarcinoma.     

Bufalin Induces Lung Cancer Cell Apoptosis via the Inhibition of PI3K/Akt Pathway

Bufalin is a class of toxic steroids which could induce the differentiation and apoptosis of leukemia cells, and induce the apoptosis of gastric, colon and breast cancer cells. However, the anti-tumor effects of bufalin have not been demonstrated in lung cancer. In this study we used A549 human lung adenocarcinoma epithelial cell line as the experimental model to evaluate the potential of bufalin in lung cancer chemotherapy. A549 cells were treated with bufalin, then the proliferation was detected by MTT assay and apoptosis was detected by flow cytometry analysis and Giemsa staining. In addition, A549 cells were treated by Akt inhibitor LY294002 in combination with bufalin and the activation of Akt and Caspase-3 as well as the expression levels of Bax, Bcl-2 and livin were examined by Western blot analysis. The results showed that Bufalin inhibited the proliferation of A549 cells and induced the apoptosis of A549 cells in a dose and time dependent manner. Mechanistically, we found that bufalin inhibited the activation of Akt. Moreover, bufalin synergized with Akt inhibitor to induce the apoptosis of A549 cells and this was associated with the upregulation of Bax expression, the downregulation of Bcl-2 and livin expression, and the activation of Caspase-3. In conclusion, our findings demonstrate that bufalin induces lung cancer cell apoptosis via the inhibition of PI3K/Akt pathway and suggest that bufalin is a potential regimen for combined chemotherapy to overcome the resistance of lung cancer cells to chemotherapeutics induced apoptosis.     

TMEM16A,a Homoharringtonine Receptor,as a Potential Endogenic Target for Lung Cancer Treatment

Lung cancer has the highest rate of incidence and mortality among all cancers. Most chemotherapeutic drugs used to treat lung cancer cause serious side effects and are susceptible to drug resistance. Therefore, exploring novel therapeutic targets for lung cancer is important. In this study, we evaluated the potential of TMEM16A as a drug target for lung cancer. Homoharringtonine (HHT) was identified as a novel natural product inhibitor of TMEM16A. Patch-clamp experiments showed that HHT inhibited TMEM16A activity in a concentration-dependent manner. HHT significantly inhibited the proliferation and migration of lung cancer cells with high TMEM16A expression but did not affect the growth of normal lung cells in the absence of TMEM16A expression. In vivo experiments showed that HHT inhibited the growth of lung tumors in mice and did not reduce their body weight. Finally, the molecular mechanism through which HHT inhibits lung cancer was explored by western blotting. The findings showed that HHT has the potential to regulate TMEM16A activity both in vitro and in vivo and could be a new lead compound for the development of anti-lung-cancer drugs.     

Complex Effects of Sertraline and Citalopram on In Vitro Murine Breast Cancer Proliferation and on In Vivo Progression and Anxiety Level

Some selective serotonin reuptake inhibitors (SSRIs), primarily sertraline, demonstrate anti-proliferative activity in malignant cell-lines and in xenografted mouse models of colorectal tumor. There is, however, a paucity of comparative studies on the anti-tumor effects of SSRIs. We compared the in vitro and in vivo effects of sertraline and citalopram on murine 4T1 breast cancer. Grafted mice were used to determine the rate of tumor growth and survival as well as the impact of stress and antidepressant treatment on tumor progression and mortality and on pro-inflammatory cytokines. Sertraline, in the micromolar range, but not citalopram, induced a significant in vitro concentration-dependent inhibition of murine 4T1 cell proliferation and splenocyte viability. In contrast, sertraline (10 mg/kg/d), enhanced in vivo tumor growth. Contrary to the study’s hypothesis, chronic mild stress did not modify tumor growth in grafted mice. The in vitro effects of sertraline on tumor growth seem to be the opposite of its in vivo effects. The impact of sertraline treatment on humans with breast cancer should be further investigated.     

Knockdown of RRM1 with Adenoviral shRNA Vectors to Inhibit Tumor Cell Viability and Increase Chemotherapeutic Sensitivity to Gemcitabine in Bladder Cancer Cells

RRM1—an important DNA replication/repair enzyme—is the primary molecular gemcitabine (GEM) target. High RRM1-expression associates with gemcitabine-resistance in various cancers and RRM1 inhibition may provide novel cancer treatment approaches. Our study elucidates how RRM1 inhibition affects cancer cell proliferation and influences gemcitabine-resistant bladder cancer cells. Of nine bladder cancer cell lines investigated, two RRM1 highly expressed cells, 253J and RT112, were selected for further experimentation. An RRM1-targeting shRNA was cloned into adenoviral vector, Ad-shRRM1. Gene and protein expression were investigated using real-time PCR and western blotting. Cell proliferation rate and chemotherapeutic sensitivity to GEM were assessed by MTT assay. A human tumor xenograft model was prepared by implanting RRM1 highly expressed tumors, derived from RT112 cells, in nude mice. Infection with Ad-shRRM1 effectively downregulated RRM1 expression, significantly inhibiting cell growth in both RRM1 highly expressed tumor cells. In vivo, Ad-shRRM1 treatment had pronounced antitumor effects against RRM1 highly expressed tumor xenografts (p < 0.05). Moreover, combination of Ad-shRRM1 and GEM inhibited cell proliferation in both cell lines significantly more than either treatment individually. Cancer gene therapy using anti-RRM1 shRNA has pronounced antitumor effects against RRM1 highly expressed tumors, and RRM1 inhibition specifically increases bladder cancer cell GEM-sensitivity. Ad-shRRM1/GEM combination therapy may offer new treatment options for patients with GEM-resistant bladder tumors.     

磁性纳米光敏剂对人癌细胞体外杀伤效应

以硫酸亚铁、三氯化铁、正硅酸乙酯和四氯化钛为原料,通过沉淀、Stöber和溶胶凝胶法,制备得到一种复合结构的磁性纳米光敏剂TiO2/Fe3O4-SiO2,通过XRD、TEM、UV-Vis DRS和磁性测试等对其结构、性质进行了表征和分析,利用四甲基偶氮唑蓝比色法（MTT法）考察了该纳米复合光敏剂对A549人肺癌细胞的体外杀伤效应和不同TiO2负载量的TiO2/Fe3O4-SiO2对A549人肺癌细胞增殖的抑制率的影响。表征分析结果表明,该纳米复合光敏剂具有核壳结构和磁性,具有可见光吸收能力,能充分响应波长在400 nm以上的可见光。体外杀伤效应评价结果表明,当光照时间为150 min时,该纳米复合光敏剂和单纯的TiO2对A549人肺癌细胞增殖的抑制率分别为摩尔分数51%和36%,该纳米复合光敏剂具有增强的光动力活性。TiO2的适宜负载量在质量分数30%。     

Versatile hybrid polyethyleneimine–mesoporous carbon nanoparticles for targeted delivery

To meet the needs of targeted drug delivery and medical imaging, uniform mesoporous carbon spheres (UMCS) were functionalized using hyperbranched polyethyleneimine (PEI) covalently linked with fluorescein isothiocyanate (FITC) and folic acid (FA). Folate-receptor-positive KB cancer cells internalized five times more nanoparticles than A549 cells deficient in folate receptors in vitro using flow cytometry and confocal microscopy. The in vivo distribution results also confirmed that the FA–PEI–FITC–UMCS nanoparticles could target the FA-positive tumors. In addition, the specifically targeted hybrid carbon nanoparticles exhibited non-cytotoxic and controlled intracellular release (pH dependent) of the loaded agents. The in vivo antitumor effect of the paclitaxel (PTX)-loaded nanoparticles was investigated in Kunming mice harboring a hepatic H22 tumor. PTX-loaded FA–PEI–UMCS nanoparticles displayed superior antitumor effects compared to other PTX formulations, and the tumor growth inhibition rate was 86.53% compared with the control group (saline) for the enhanced targeted accumulation of NPs in tumor cells.     

Surface modified cellulose nanocrystalline hybrids actualizing efficient and precise delivery of doxorubicin into nucleus with: In vitro and in vivo evaluation

Rod-like-shape nanomedicines with the ability of lysosomal pH-controlled drug release can precisely deliver doxorubicin (DOX) into its target, nucleus, and can fully exert its anticancer effect. Taking advantage of their large specific surface area, cellulose nanocrystals (CNCs) were used to fabricate pH-responsive DOX-loaded rod-like shaped hybrids nanomedicines: cis-aconityl-doxorubicin (CAD)@polyethylenimine (PEI)@CNCs (CAD@PEI@CNCs) via layer-by-layer (LbL) assembly. In vitro, CAD@PEI@CNCs hybrids displayed rod-like shape, high drug loading content, lysosomal pH-controlled drug release, efficient and precise doxorubicin (DOX) delivering into the nucleus. Moreover, the cellular uptake of CAD@PEI@CNCs hybrids was 20.9 folds higher than that of DOX·HCl against A549 cells. The cytotoxicity of CAD@PEI@CNCs hybrids was much higher than that of DOX·HCl and the pH-irresponsive hybrids against A549 cell. In vivo, CAD@PEI@CNCs hybrids exhibited good antitumor effect: (42.0 ± 6)% inhibition rate and few harms to the nude mice. Altogether, rod-like shaped pH-responsive CAD@PEI@CNCs hybrids nanomedicines could efficiently overcome the vascular and tumor barriers, and precisely deliver DOX to nucleus to convert DOX antitumor effects. These results indicate that CAD@PEI@CNCs have great potential to act as advanced nanomedicines with enhanced delivery efficiency and therapeutic efficiency.     

Synthetic Circular miR-21 Sponge as Tool for Lung Cancer Treatment

Lung cancer is the most common cancer in the world and several miRNAs are associated with it. MiRNA sponges are presented as tools to inhibit miRNAs. We designed a system to capture miRNAs based on circular RNAs (circRNA). To demonstrate its usefulness, we chose miR-21, which is upregulated and implicated in lung cancer. We constructed a miR-21 sponge and inserted it into a vector that facilitates circular RNA production (Circ-21) to study its effect on growth, colony formation, and migration in lung cancer cell lines and multicellular tumor spheroids (MTS). Circ-21 induced a significant and time-dependent decrease in the growth of A549 and LL2 cells, but not in L132 cells. Furthermore, A549 and LL2 cells transfected with Circ-21 showed a lower number of colonies and migration than L132. Similar findings were seen in A549 and LL2 Circ-21 MTS, which showed a significant decrease in volume growth, but not in L132 Circ-21 MTS. Based on this, the miR-21 circular sponge may suppress the processes of tumorigenesis and progression. Therefore, our system based on circular sponges seems to be effective, as a tool for the capture of other miRNAs.     

Effects of a Unique Combination of the Whole-Body Low Dose Radiotherapy with Inactivation of Two Immune Checkpoints and/or a Heat Shock Protein on the Transplantable Lung Cancer in Mice

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer death worldwide. Recently, targeting molecules whose functions are associated with tumorigenesis has become a game changing adjunct to standard anti-cancer therapy. As evidenced by the results of preclinical and clinical investigations, whole-body irradiations (WBI) with X-rays at less than 0.1–0.2 Gy per fraction can induce remissions of various neoplasms without inciting adverse side effects of conventional chemo- and radiotherapy. In the present study, a murine model of human NSCLC was employed to evaluate for the first time the anti-neoplastic efficacy of WBI combined with inactivation of CTLA-4, PD-1, and/or HSP90. The results indicate that WBI alone and in conjunction with the inhibition of the function of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed death-1 (PD-1) receptor immune checkpoints (ICs) and/or heat shock protein 90 (HSP90) markedly reduced tumorigenesis in mice implanted by three different routes with the syngeneic Lewis lung cancer cells and suppressed clonogenic potential of Lewis lung carcinoma (LLC1) cells in vitro. These results were associated with the relevant changes in the profile of pro- and anti-neoplastic immune cells recruited to the growing tumors and the circulating anti- and pro-inflammatory cytokines. In contrast, inhibition of the tested molecular targets used either separately or in combination with each other did not exert notable anti-neoplastic effects. Moreover, no significant synergistic effects were detected when the inhibitors were applied concurrently with WBI. The obtained results supplemented with further mechanistic explanations provided by future investigations will help design the effective strategies of treatment of lung and other cancers based on inactivation of the immune checkpoint and/or heat shock molecules combined with low-dose radiotherapy.     

Preclinical Evaluation of Sodium Selenite in Mice: Toxicological and Tumor Regression Studies after Striatum Implantation of Human Glioblastoma Stem Cells

Glioblastoma (GBM) is the most aggressive malignant glioma, with a very poor prognosis; as such, efforts to explore new treatments and GBM’s etiology are a priority. We previously described human GBM cells (R2J-GS) as exhibiting the properties of cancer stem cells (growing in serum-free medium and proliferating into nude mice when orthotopically grafted). Sodium selenite (SS)—an in vitro attractive agent for cancer therapy against GBM—was evaluated in R2J-GS cells. To go further, we launched a preclinical study: SS was given orally, in an escalation-dose study (2.25 to 10.125 mg/kg/day, 5 days on, 2 days off, and 5 days on), to evaluate (1) the absorption of selenium in plasma and organs (brain, kidney, liver, and lung) and (2) the SS toxicity. A 6.75 mg/kg SS dose was chosen to perform a tumor regression assay, followed by MRI, in R2J-GS cells orthotopically implanted in nude mice, as this dose was nontoxic and increased brain selenium concentration. A group receiving TMZ (5 mg/kg) was led in parallel. Although not reaching statistical significance, the group of mice treated with SS showed a slower tumor growth vs. the control group (p = 0.08). No difference was observed between the TMZ and control groups. We provide new insights of the mechanisms of SS and its possible use in chemotherapy.     

Pro‐oxidant and Antioxidant Effects in Photodynamic Therapy: Cells Recognise that Not All Exogenous ROS Are Alike

Photodynamic therapy (PDT) uses light, photosensitizer molecules and oxygen to generate reactive oxygen species (ROS) that kill cancer cells. Redaporfin, a new photosensitizer in clinical trials, generates both singlet oxygen and superoxide ions. We report the potentiation of redaporfin–PDT in combination with ascorbate and with the inhibition of antioxidant enzymes in A549 (human lung adenocarcinoma) and CT26 (mouse colon adenocarcinoma) cells. The addition of ascorbate and the inhibition of superoxide dismutase (SOD) strongly increased the phototoxicity of redaporfin towards A549 cells but not towards CT26 cells. The inhibition of catalase and the depletion of the glutathione pool also potentiate redaporfin–PDT towards A549 cells. The lower SOD activity of A549 cells might explain this difference. SOD activity levels may be explored to increase the selectivity and efficacy of PDT with photosensitizers that generate radical species.     

Myricanol Induces Apoptotic Cell Death and Anti-Tumor Activity in Non-Small Cell Lung Carcinoma in Vivo

This study explored the inhibiting effect and mechanism of myricanol on lung adenocarcinoma A549 xenografts in nude mice. Forty nude mice with subcutaneous A549 xenografts were randomly divided into five groups: high-dose myricanol (40 mg/kg body weight) group; middle-dose myricanol (20 mg/kg body weight) group; low-dose myricanol (10 mg/kg body weight) group; polyethylene glycol 400 vehicle group (1 mL/kg); and tumor model group. Nude mice were sacrificed after 14 days of treatment and the tumor inhibition rate (TIR, %) was then calculated. The relative mRNA expression levels of Bax, Bcl-2, VEGF, HIF-1α, and survivin in the tumor tissues were determined by real-time PCR. TUNEL assay was applied to determine cellular apoptosis, while IHC test was performed to detect the protein expression levels of Bax, Bcl-2, VEGF, HIF-1α, and survivin. The TIR of the three myricanol-treated groups ranged from 14.9% to 38.5%. The IHC results showed that the protein expression of Bcl-2, VEGF, HIF-1α, and survivin were consistently downregulated, whereas that of Bax was upregulated after myricanol treatment. Myricanol also significantly upregulated the mRNA expression of Bax and downregulated that of Bcl-2, VEGF, HIF-1α, and survivin in a dose-dependent manner (p < 0.05 to 0.001). These results are consistent with those of IHC. The TUNEL assay results indicated that apoptotic-positive cells significantly increased in the myricanol-treated tumor tissues compared with the cells of the vehicle control group (p < 0.01 to 0.001). These data suggest that myricanol could significantly decelerate tumor growth in vivo by inducing apoptosis.     

Canola Oil Inhibits Breast Cancer Cell Growth in Cultures and In Vivo and Acts Synergistically with Chemotherapeutic Drugs

Certain fatty acids in canola oil (CAN) have been associated with a reduced risk of breast cancer. This study assessed the effects of CAN on proliferation and death of human breast cancer cells in vitro and in vivo in chemically induced mammary carcinogenesis. We hypothesize that CAN reduces breast cancer cell growth by inducing cell death. In a series of in vitro experiments, human breast cancer T47D and MCF-7 cells were cultured and treated with CAN and two chemotherapeutic drugs, tamoxifen and cerulenin. Cell proliferation and caspase-3 and p53 activities were measured. Reduced cancer cell growth and increased expression of caspase-3 and p53 were seen in T47D and MCF-7 cells treated with CAN. Moreover, CAN showed synergistic cancer cell growth inhibition effects with tamoxifen and cerulenin. In a subsequent live animal experiment, 42 female Sprague–Dawley rats were randomly assigned to corn oil (CORN) or CAN diets, and mammary tumors were chemically induced by N-nitroso-N-methylurea. CAN-dieted rats had reduced tumor volumes and showed an increased survival rate as compared to CORN-dieted rats. We demonstrated that CAN has suppressive effects on cancer growth, and reduces tumor volumes. The results suggest that CAN may have inhibitory effects on breast cancer cell growth, and warrants further investigation of the synergistic effects of CAN with anti-cancer drugs.     

Coriloxin Exerts Antitumor Effects in Human Lung Adenocarcinoma Cells

Both in Taiwan and around the world, lung cancer is a primary cause of cancer-related deaths. In Taiwan, the most prevalent form of lung cancer is lung adenocarcinoma, a type of non-small-cell lung carcinoma. Although numerous lung cancer therapies are available, their clinical outcomes are unsatisfactory. Natural products, including fungal metabolites, are excellent sources of pharmaceutical compounds used in cancer treatment. We employed in vitro cell invasion, cell proliferation, cell migration, cell viability, and colony formation assays with the aim of evaluating the effects of coriloxin, isolated from fermented broths of Nectria balsamea YMJ94052402, on human lung adenocarcinoma CL1-5 and/or A549 cells. The potential targets regulated by coriloxin were examined through Western blot analysis. The cytotoxic effect of coriloxin was more efficiently exerted on lung adenocarcinoma cells than on bronchial epithelial cells. Moreover, low-concentration coriloxin significantly suppressed adenocarcinoma cells’ proliferative, migratory, and clonogenic abilities. These inhibitory effects were achieved through ERK/AKT inactivation, epithelial–mesenchymal transition regulation, and HLJ1 expression. Our findings suggest that coriloxin can be used as a multitarget anticancer agent. Further investigations of the application of coriloxin as an adjuvant therapy in lung cancer treatment are warranted.