Induction of the apoptosis of cancer cell by sonodynamic therapy:a review

Ultrasound can be used not only in examination, but also in therapy, especially in the therapy of cancer. Sonodynamic therapy is an experimental cancer therapy method which uses ultrasound to enhance the cytotoxic effects of agents known as sonosensitizers. It has been tested in vitro and in vivo. The ultrasound could penetrate the tissue and cell under some of conditions which directly changes cell membrane permeability, thereby allowing the delivery of exogenous molecules into the cells in some degree. Ultrasound could inhibit the proliferation or induce the apoptosis of cancer cells in vitro or in vivo. Recent researches indicated low-frequency and low-intensity ultrasound could induce cell apoptosis, which could be strengthened by sonodynamic sensitivity, microbubbles, chemotherapeutic drugs and so on. Most kinds of ultrasound suppressed the proliferation of cancer cells through inducing the apoptosis of cancer cells. The mechanism of apoptosis is not clear. In this review, we will focus on and discuss the mechanisms of the induction of cancer cell apoptosis by ultrasound.

Influence of Photodynamic Therapy on Apoptosis and Invasion of Human Cholangiocarcinoma QBC939 Cell Line

Objective To investigate the effect of photodynamic therapy(PDT) mediated by hematoporphyrin derivative(HPD) on apoptosis and invasion of cholangiocarcinoma QBC939 cell lines. Methods In vitro cultured cholangiocarcinoma QBC939 cell line was exposed to 2, 4, 6, 8, 10, 12, and 14 μg/ml HPD with 5, 10, and 15 J/cm2 light intensity, respectively. The optical density at 450 nm of the QBC939 cells was measured by CCK8 assay and its growth inhibition ratio was calculated. Flow cytometry and transwell migration assay were applied to detect cell apoptosis and invasion respectively. RT-PCR and immunocytochemistry analyses were used to detect expressions of vascular endothelial growth factor-C(VEGF-C), cyclooxygenase-2(COX-2), and proliferating cell nuclear antigen(PCNA). Enzyme-linked immunosorbent assay(ELISA) was carried out to examine the secretion of VEGF-C and COX-2 in QBC939 cells. Results Exposure to HPD-PDT can significantly suppress the growth of QBC939 cells(all P<0.05). HPD-PDT can promote apoptosis of QBC939 cells at the early stage. When the concentration of HPD was 2 μg/ml and light irradiation was 5 J/cm2, HPD-PDT had no obvious inhibitory effect on QBC939 cell growth, but can obviously inhibit cell invasion, and significant difference was observed between the HPD-PDT and control groups(P<0.01). The HPD-PDT can reduce the m RNA and protein expressions of VEGF-C, COX-2, and PCNA, and decrease the secretion of VEGF-C and COX-2 in QBC939 cells. Conclusion PDT could promote apoptosis and inhibit growth and invasion of cholangiocarcinoma cells QBC939 in vitro.

Apoptosis block as a barrier to effective therapy in non small cell lung cancer

Lung cancer, is the most common cause of cancer death in men and second only to breast cancer in women. Currently, the first line therapy of choice is platinumbased combination chemotherapy. A therapeutic plateau has been reached with the prognosis for patients with advanced non-small cell lung cancer(NSCLC) remaining poor. New biomarkers of prognosis as well as new therapies focusing on molecular targets are emerging helping to identify patients who are likely to benefit from therapy. Despite this, drug resistance remains the major cause for treatment failure. In this article we review the role of apoptosis in mediating drug resistance in NSCLC. Better understanding of this fundamental biological process may provide a rationale for overcoming the current therapeutic plateau.

Targeted IL-24 gene therapy inhibits cancer recurrence after liver tumor resection by inducing tumor cell apoptosis in nude mice

BACKGROUND: Interleukin-24 (IL-24) is a novel candidate tumor suppressor that induces tumor cell apoptosis experimentally in a variety of human malignant cells including liver cancer cells. The present study was conducted to investigate the potential effect of recombinant adeno-associated virus (rAAV)-mediated IL-24 gene therapy on tumor recurrence and metastasis by inducing tumor cell apoptosis in a hepatocellular carcinoma (HCC) model in nude mice. METHODS: We established a recurrent and metastatic HCC model in nude mice and constructed an rAAV vector carrying alpha-fetoprotein (AFP) promoter for expressing the IL-24 gene (rAVV/AFP/IL-24). The vector was administered by regional injection (liver incisal margin). AFP was detected by radiation immunoassay. Histological evaluation of tumor recurrence and metastasis was performed for the liver and lung. The effect of tumor cell apoptosis was confirmed by TUNEL analysis. RESULTS: IL-24 gene therapy prevented tumor recurrence and metastasis, as evidenced by marked decreases in the number of metastatic tumor nodules and tumor volume in the liver and lung. At the same time, serum AFP concentration decreased markedly in the IL-24 group compared with the control or rAAV groups (P<0.05). IL-24 gene therapy inhibited tumor recurrence and metastasis as evidenced by the induction of tumor cell apoptosis. CONCLUSION: The results demonstrated that targeted IL-24 gene therapy was effective in the prevention of postoperative recurrence and metastasis in an HCC nude mice model by induction of tumor cells apoptosis with potential minimum tumor burden.

Early apoptosis and cell death induced by ATX-S10Na(Ⅱ)-mediated photodynamic therapy are Bax- and p53-dependent in human colon cancer cells

AIM: To investigate the roles of Bax and p53 proteins in photosensitivity of human colon cancer cells by using lysosome-localizing photosensitizer, ATX-S10Na (Ⅱ).METHODS: HCT116 human colon cancer cells and Bax-null or p53-null isogenic derivatives were irradiated with a diode laser. Early apoptosis and cell death in response to photodynamic therapy were determined by MTT assays, annexin V assays, transmission electron microscopy assays, caspase assays and western blotting.RESULTS: Induction of early apoptosis and cell death was Bax- and p53-dependent. Bax and p53 were required for caspase-dependent apoptosis. The levels of anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-xL, were decreased in Bax- and p53-independent manner.CONCLUSION: Our results indicate that early apoptosis and cell death of human colon cancer cells induced by photodynamic therapy with lysosome-localizing photosensitizer ATX-S10Na (Ⅱ) are mediated by p53-Bax network and low levels of Bcl-2 and Bcl-xL proteins. Our results might help in formulating new therapeutic approaches in photodynamic therapy.

Antitumor effects of a novel photosensitizer-mediated photodynamic therapy and its influence on the cell transcriptome

Photodynamic therapy(PDT)is a promising cancer treatment.This study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]−10,15,20-triphenyl-porphyrin(DTP)mediated PDT(DTP-PDT).Cell viability,reactive oxygen species(ROS),and apoptosis were measured with a Cell Counting Kit-8 assay,DCFH-DA fluorescent probe,and Hoechst staining,respectively.Cell apoptosis-and autophagy-related proteins were examined using western blotting.RNA sequencing was used to screen differentially expressed mRNAs(DERs),and bioinformatic analysis was performed to identify the major biological events after DTP-PDT.Our results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 cells.The ROS scavenger N-acetyl-L-cysteine(NAC)and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced cytotoxicity.DTP-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2,which could also be inhibited by NAC or SB203580.The level of LC3B-Ⅱ,a marker of autophagy,was increased by DTP-PDT.A total of 3496 DERs were obtained after DTP-PDT.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes,the nuclear lumen,protein binding,cell cycle,protein targeting to the endoplasmic reticulum,and ribosomal DNA replication.Disease Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle checkpoints.Protein-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting genes.Therefore,DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy,partly through ROS and the P38 MAPK signaling pathway.Genes associated with the cell cycle,ribosomes,DNA replication,and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity.

Effect of adjuvant therapy with ginkgo-damole on apoptosis, nerve injury and platelet aggregation of patients with acute cerebral infarction

Objective:To investigate the effect of adjuvant therapy with ginkgo-damole on apoptosis, nerve injury and platelet aggregation of patients with acute cerebral infarction. Methods:A total of 74 patients with acute cerebral infarction treated in our hospital from March 2014 to December 2015 were retrospectively analyzed, and they were divided into ginkgo-damole group and conventional treatment group according to a therapeutic schedule that whether ginkgo-diyidamolum were included. At Week 2 and Week 4 after treatment, contents of apoptosis molecule, nerve injury molecule and index of platelet aggregation in serum were detected. Results:At Week 2 after treatment, contents of soluble Fas, soluble Fas ligand, soluble tumor necrosis factor related apoptosis inducing ligand, S100β, neuron specific enolase, glial fibrillary acidic protein, myelin basic protein, malonaldehyde, endothelin-1, fibrinogen and D-dimer in patients' sera of ginkgo-damole group were significantly lower than those of conventional treatment group. Contents of nitric oxide in sera were obviously higher than that of conventional treatment group. At Week 4 after treatment, contents of soluble Fas, soluble Fas ligand, soluble tumor necrosis factor related apoptosis inducing ligand, S100β, neuron specific enolase, glial fibrillary acidic protein, myelin basic protein, malonaldehyde, endothelin-1, fibrinogen and D-dimer in patients' sera of ginkgo-damole group were significantly lower than those of conventional treatment group. Contents of nitric oxide in sera were obviously higher than that of conventional treatment group. Conclusions:Adjuvant therapy with ginkgo-damole can inhibit the apoptosis of neuron cells and neurogliocyte and reduce the neural function injury and the situation of platelet aggregation.

Platelet therapy:A novel strategy for liver regeneration,anti-fibrosis,and anti-apoptosis

Platelets contain bio-physiological substances, including insulin-like growth factor-1, vascular endothelial growth factor, platelet-derived growth factor,hepatocyte growth factor, serotonin, transforming growth factor-β, adenosine diphosphate, adenosine tri-phosphate, and epidermal growth factor. Platelets have conventionally been considered to exacerbate the inflammatory response and liver injury. Recently,platelets were discovered to have a positive impact on the liver. In this review, we present experimenta and clinical evidence indicating that platelets accelerate liver regeneration and have anti-fibrosis and antiapoptosis activity, and we detail the mechanisms of action. Platelets accelerate liver regeneration by three different mechanisms:(1) a direct effect on hepatocytes,(2) a cooperative effect with liver sinusoidal endothelial cells, and(3) a collaborative effect with Kupffer cells. Platelets exert anti-fibrotic activity by deactivating hepatic stellate cells via the adenosinecyclic adenosine 5'-monophosphate signaling pathway.Platelets prevent hepatocyte apoptosis by activating the Akt pathway and up-regulating Bcl-x L, which sup-presses caspase-3 activation. Platelet therapy with thrombopoietin, thrombopoietin receptor agonists, and platelet transfusion has the advantages of convenience and cost-efficiency over other treatments. We propose that in the future, platelet therapy will play a promising role in the treatment of the various liver disorders that currently challenge the surgical field, such as liver failure after a massive hepatectomy, hepatectomy of a cirrhotic liver, and small grafts in liver transplantation.

Effects of intensity modulated radiation therapy + local hyperthermia on the cancer cell apoptosis and invasion in liver cancer lesion

Objective: To investigate the effects of intensity modulated radiation therapy + local hyperthermia on the cancer cell apoptosis and invasion in liver cancer lesion. Methods:A total of 94 patients with middle-advanced primary liver cancer who were diagnosed and treated in this hospital between November 2015 and February 2017 were divided into control group (n=47) and experimental group (n=47) by random number table method. Control group received intensity modulated radiation therapy and experimental group received intensity modulated radiation therapy + local hyperthermia. Both groups accepted peritoneal lesion biopsy before and after treatment, and the expression of apoptosis and invasion genes in specimen tissue were detected by fluorescence quantitative PCR. Results: There was no statistically significant difference in apoptosis and invasion gene expression between the two groups of patients before treatment. After treatment, apoptosis genes Fas, caspase-3, Bax and p53 mRNA expression in lesion tissue of experimental group were higher than those of control group whereas FasL and Bcl-2 mRNA expression were lower than those of control group;invasion genes Cofilin-1, Bmi-1, STAT3 and SOX18 mRNA expression in lesion tissue of experimental group were lower than those of control group whereas Tip30 and TP53IP1 mRNA expression were higher than those of control group. Conclusion: intensity modulated radiation therapy + local hyperthermia can effectively promote cancer cell apoptosis and inhibit its invasion activity in patients with middle and advanced primary liver cancer.

Function of apoptosis and expression of the proteins Bcl-2,p53 and C-myc in the development of gastric cancer

INTRODUCTIONIn China ,the incidence and mortality of gastric cancer rank the second among all cancers. Recent development of cancer [1-20].The aim of this study was investigat the insight of apoptosis and bcl-2, p53 and C-myc protein expression in the development of gastric cancer .

Telmisartan induces melanoma cell apoptosis and synergizes with vemurafenib in vitro by altering cell bioenergetics

Objective: Despite recent advancements in targeted therapy and immunotherapies, prognosis for metastatic melanoma patients remains extremely poor. Development of resistance to previously effective treatments presents a serious challenge and new approaches for melanoma treatment are urgently needed. The objective of this study was to examine the effects of telmisartan, an AGTR1 inhibitor and a partial agonist of PPARγ, on melanoma cells as a potential agent for repurposing in melanoma treatment.Methods: Expression of AGTR1 and PPARγ m RNA in melanoma patient tumor samples was examined in publicly available datasets and confirmed in melanoma cell lines by qRT-PCR. A panel of melanoma cell lines was tested in viability, apoptosis and metabolic assays in presence of telmisartan by flow cytometry and immunocytochemistry. A cytotoxic effect of combinations of telmisartan and targeted therapy vemurafenib was examined using the Chou-Talalay combination index method.Results: Both AGTR1 and PPARγ mRNA were expressed in melanoma patient tumor samples and decreased compared to the expression in the healthy skin. In vitro, we found that telmisartan decreased melanoma cell viability by inducing cell apoptosis.Increased glucose uptake, but not utilization, in the presence of telmisartan caused the fission of mitochondria and release of reactive oxygen species. Telmisartan altered the cell bioenergetics, thereby synergizing with vemurafenib in vitro, and even sensitized vemurafenib-resistant cells to the treatment.Conclusions: Given that the effective doses of telmisartan examined in our study can be administered to patients and that telmisartan is a widely used and safe antihypertensive drug, our findings provide the scientific rationale for testing its efficacy in treatment of melanoma progression.

A viral vector expressing hypoxia-inducible factor 1 alpha inhibits hippocampal neuronal apoptosis

Hypoxia-inducible factor 1 （HIF-1） attenuates amyloid-beta protein neurotoxicity and decreases apoptosis induced by oxidative stress or hypoxia in cortical neurons. In this study, we construct-ed a recombinant adeno-associated virus （rAAV） vector expressing the human HIF-1αgene （rAAV-HIF-1α）, and tested the assumption that rAAV-HIF-1αrepresses hippocampal neuronal apoptosis induced by amyloid-beta protein. Our results conifrmed that rAAV-HIF-1αsigniifcant-ly reduces apoptosis induced by amyloid-beta protein in primary cultured hippocampal neurons. Direct intracerebral rAAV-HIF-1αadministration also induced robust and prolonged HIF-1αproduction in rat hippocampus. Single rAAV-HIF-1αadministration resulted in decreased apoptosis of hippocampal neurons in an Alzheimer＇s disease rat model established by intrace-rebroventricular injection of aggregated amyloid-beta protein （25-35）. Our in vitro and in vivo ifndings demonstrate that HIF-1 has potential for attenuating hippocampal neuronal apoptosis induced by amyloid-beta protein, and provides experimental support for treatment of neurode-generative diseases using gene therapy.

Replication-incompetent Adenovirus Vector-mediated MDA-7/IL-24 Selectively Induces Growth Suppression and Apoptosis of Hepatoma Cell Line SMMC-7721

In order to investigate the effect of replication-incompetent adenovirus vector expressing MDA-7/IL-24 on tumor growth and apoptosis of human hepatocellular carcinoma （HCC） cell line SMMC-7721 and normal liver cell line L02, the recombinant replication-incompetent Ad.mda-7 virus vector was constructed and infected into the HCC cell line SMMC-7721 and normal liver cell line L02. RT-PCR was performed to examine the expression of MDA-7 mRNA. The concentrations of MDA-7/IL-4 in culture superuatants were determined by using ELISA. MTT and Hoechst staining assay were applied to observe the inhibitory and killing effects of MDA-7 on the HCC cells. By using flow cytometry, the apoptosis, cell cycle and proliferation of SMMC-7721 and L02 cells were measured. The results showed recombinant replication-incompetent virus expressing MDA-7/IL-24 was constructed successfully, and RT-PCR revealed that it could mediate the high expression of the exogenous gene MDA-7/IL-24 in SMMC-7721 and L02 cells. The expression of MDA-7/IL-24 proteins in the culture superuatant was detectable by ELISA. Ad.mda-7 infection induced apoptosis and growth suppression in SMMC-7721 cells and an increased percentage of HCC cells in the GyM phase of the cell cycle, but not in L02 cells. It was concluded that mda-7/IL-24 gene, mediated with replication-incompetent adenovirus vector, could selectively induce growth suppression and apoptosis in HCC cell line SMMC-7721 but without any toxic side-effect on normal liver line L02.

Relationship between Fas/ FasL expression and apoptosis of colon adenocarcinoma cell lines

INTRODUCTIONFas/ FasL system has been identified as a keymediator of apoptosis in tumor cells[1-4]. Theoccurrence and development of neoplasm are closelyrelated to apoptosis[5-7] Most chemotherapeuticdrugs kill cancer cells mainly by inducingapoptosis[8-14].'

VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis

脉管的 endothelial 细胞生长禁止者(VEGI ) 是肿瘤坏死因素总科的一个成员并且在脉管的动态平衡起一个重要作用。在这研究，调查 anticancer 这基因的治疗学的潜力， VEGI (VEGI-251 ) 的分泌 isoform 与 E1B 55 kDa 基因删除(ZD55 ) 被插入到有选择地复制的侵入人体气管粘膜的病菌构造 ZD55-VEGI-251。我们这里报导 potently 从 ZD55-VEGI-251-infected 癌症房间生产的分泌 VEGI-251 禁止 endothelial 房间增长，在在 vivo 的小鸡 chorioallantoic 膜的 vitro 和 angiogenesis 的试管形成。另外， ZD55-VEGI-251 感染在几根人的癌症房间线上比控制病毒导致更严重的 cytopathic 效果，包括颈的癌症房间线 HeLa， hepatoma 房间线 SMMC-7721 和 colorectal 癌症房间线 SW620。进一步的学习表明增加的 cytotoxicity 是 caspase-9 激活，提高的 caspase-3 激活和 PARP 劈开伴随的 VEGI-251 autocrine 依赖的、调停线粒体的 apoptosis 的结果。而且，显著地忍受颈的人和 colorectal 肿瘤异种皮移植的 athymic 裸体人老鼠的 ZD55-VEGI-251-treatment 压制了肿瘤生长。我们的调查结果显示 antiangiogenesis 和 apoptosis 感应的活动的联合效果为癌症使 VEGI-251-armed oncolytic 侵入人体气管粘膜的病菌成为一个有希望的治疗学的代理人。

Apoptosis in oncology

Apoptosis is a complex process involving a large array of genes and mutation of any of these genes may lead to malignancy formation. Re-acquirement of FasL by tumor cells may enable them to evade the surveillance of immune system and thus contributes to the growth of tumor. Apart from traditional therapies, inducing apoptosis of tumor cell by new methods employing death receptor ligands and making use of Fas counterattack is also being developed.

Melanoma differentiation-associated gene-7, MDA-7/IL-24, selectively induces growth suppression, apoptosis in human hepatocellular carcinoma cell line HepG2 by replication-incompetent adenovirus vector

瞄准：调查在人的肝细胞在肿瘤生长和 apoptosis 上表示 MDA-7/IL-24 的复制无能的侵入人体气管粘膜的病菌向量的效果癌(HCC ) 房间线 HepG2 和正常的肝房间衬里 L02。方法：我们构造了 recombinant 复制无能的 Ad.mda-7 病毒向量并且感染了它进人的 HCC 房间线 HepG2 和正常的肝房间线 L02。RT-PCR 被执行检测在房间表示的 mRNA。被 ELISA 用来在文化上层清液检测 MDA-7/IL-24 蛋白质表示。Ad.mda-7 导致的 apoptosis 的效果被 Hoechst 与染色的 Annexin-V 和 PI 染色和流动血细胞计数试金证实。MTT 试金被用来决定 HepG2 细胞的生长抑制，并且房间周期和 hypodiploidy 分析被流动血细胞计数执行。结果：Recombinant 复制有缺陷者病毒表示 MDA-7/IL-24 成功地被构造。RT-PCR 证明 Ad.mda-7 能调停进 HepG2 和 L02 的外长的基因 MDA-7/IL-24 的表示。在上层清液的 MDA-7/IL-24 蛋白质的集中分别地在 Ad.mda-7-infected L02 和 HepG2 房间是 130 pg/mL 和 110 pg/mL。 Ad.mda-7 感染显然导致了 apoptosis (从2.60%+/-0.72%到33.6%+/-13.2%， P=0.00012 )并且在 HepG2 (抑制比率IR=68%)的生长抑制和在房间的 G2/M 阶段的特定的癌症房间类型的百分比的增加骑车(从6.44%～32.29%， P【0.01 )，然而并非在 L02 房间。结论：这些结果有选择地在人的肝细胞癌细胞线 HepG2 与复制无能的侵入人体气管粘膜的病菌向量由 mda-7/IL-24 基因证实 apoptosis 和生长抑制的正式就职。

The neuroprotective effects of oxygen therapy in Alzheimer’s disease:a narrative review

Alzheimer’s disease(AD)is a degenerative neurological disease that primarily affects the elderly.Drug therapy is the main strategy for AD treatment,but current treatments suffer from poor efficacy and a number of side effects.Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD.Hypoxia is one of the important factors that contribute to the pathogenesis of AD.Multiple cellular processes synergistically promote hypoxia,including aging,hypertension,diabetes,hypoxia/obstructive sleep apnea,obesity,and traumatic brain injury.Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD,such as amyloid-beta metabolism,tau phosphorylation,autophagy,neuroinflammation,oxidative stress,endoplasmic reticulum stress,and mitochondrial and synaptic dysfunction.Treatments targeting hypoxia may delay or mitigate the progression of AD.Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD.Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism,tau phosphorylation,neuroinflammation,neuronal apoptosis,oxidative stress,neurotrophic factors,mitochondrial function,cerebral blood volume,and protein synthesis.In this review,we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations.We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.