Promote Tumor Cell Apoptosis Research Articles

Study on the mechanism of Sorafenib combined with Bevacizumab on the tumor inhibition of cervical cancer cell line U14 transplantation in mice

Objective According to effect of Sorafenib combined Bevacizumab in mice U14 cervical cancer cell lines, observe the changes of cell lines of transplanted tumor U14 cell structure and adjustment effect of Bcl-2 and Bax protein expression. Methods Sixty female 615 mice of healthy inbreeding line, aged from 4 to 6 weeks, average weight is 20.4 g, range from 18 to 25 g. The animals were divided into blank control group (group A)with 10 mice, and U14 cervical cancer cell lines by vaccinating mice a tumor-burdened mice model was established, on the 6th day after subcutaneous inoculation of U14, 40 tumor-burdened mice with tumor diameter ≥ 5 mm were selected. The mice were divided into 5 groups according to the completely randomized grouping method: model group (group B), Sorafenib group (group C), low-dose Bevacizumab combined with Sorafenib group (group D), the middle dose Bevacizumab combined with Sorafenib group (group E), and the high dose Bevacizumab combined with Sorafenib group (group F), 8 mice in each group. The treatment regimen consisted of 1 ml of 0.9% sodium chloride solution in group A and group B, Sorafenib 12 mg/kg in group C, and Bevacizumab 2.5 mg/kg + Sorafenib 12 mg/kg in group D, Bevacizumab 5 mg/kg+ Sorafenib 12 mg/kg in group E, and Bevacizumab 10 mg/kg + Sorafenib 12 mg/kg in group F. All mice were injected intraperitoneally and sacrificed by dislocation 24 days later. The tumor weight (g) was measured every 6 days, and the body weight of each group was observed, and calculated the tumor inhibition rate of each group of mice. The histopathological changes of the transplanted mice were observed by hematoxylin-eosin staining. The transplantation of each group of mice was observed by electron microscope. Morphological changes of tumor tissue; the expression of Bcl-2 and Bax protein in each group were observed by immunohistochemistry. The measurement data were expressed as mean standard deviation(Mean±SD), univariate analysis of variance was used for inter-group comparison, and LSD method was used for pairwise comparison. Results At the beginning of the intraperitoneal injection of the drug, the body weight of the mice began to increase slowly and continuously, and the trend of the mice in each group was basically the same. The tumor inhibition rate of group C was 8.02%, 4.92% in group D, 11.10% in group E, and 5.42% in group F. Group E had the highest tumor inhibition rate and the best effect. The difference in tumor weight between group A and the other groups was statistically significant (P<0.05). The results of electron microscopy showed that the cell structure changes in C, D, E and F groups were similar, and the apoptosis of tumor cells appeared after treatment. The apoptosis of group E was the best. The apoptosis-related proteins in group C, D, E and F were observed. The expression of Bax was up-regulated, and the positive number in group E was the highest. The expression of proto-oncogene Bcl-2 was down-regulated in group C, D, E and F, and the number of positive in group E was the least, and the difference was statistically significant (P<0.05). Conclusions Sorafenib combined with Bevacizumab can promote tumor cell apoptosis by up-regulating Bax and down-regulating Bcl-2 protein expression. Among them, Sorafenib combined with Bevacizumab at medium dose promotes tumor cell apoptosis better than other methods, providing a basis for clinical treatment. Key words: Uterine cervical neoplasms; Antineoplastic combined chemotherapy protocols; Drug therapy, combination; Genes, bcl-2; Bax protein; Rats

Toosendanin induces the apoptosis of human Ewing's sarcoma cells via the mitochondrial apoptotic pathway.

Toosendanin, a triterpenoid extracted from the root bark of Melia toosendan, has its origin from traditional Chinese medicine and has been used as a non-polluting and pesticide-free plant insecticide in China for fruit and vegetable production. In recent years, toosendanin has been found to inhibit tumor cell proliferation and promote tumor cell apoptosis. Ewing's sarcoma (ES) is the second most common primary malignant bone and soft tissue tumor in children and adolescents. Although the overall prognosis of ES has improved, the 5-year survival rate has not significantly increased. To analyze the role of toosendanin on ES progression, CCK-8 viability assay, flow cytometry, Hoechst 33258 staining and western blotting were performed. The present results suggested that toosendanin suppressed cell viability and induced apoptosis in human SK-ES-1 cells compared with DMSO treatment. In addition, in the present study, toosendanin was found to upregulate the expression of Bax and downregulate the expression of Bcl-2, altering the Bax/Bcl-2 ratio. Additionally, toosendanin promoted the release of cytochrome c, resulting in the activation of the mitochondrial apoptotic pathway, thus inducing the activation of caspase-9 and caspase-3, and the cleavage of PARP. Our results demonstrated that toosendanin inhibited the growth of ES cells in a dose-dependent manner and triggered mitochondrial apoptotic pathway to induce apoptosis. Therefore, toosendanin can potentially be utilized as an anticancer botanical drug for the treatment of ES.

New progress in the anti-tumor mechanism of curcumin

Curcumin is derived from traditional Chinese medicine turmeric and can be used for chemoprevention and treatment of various cancers. Recent studies have shown that curcumin can participate in the regulation of various molecular signal transduction pathways, regulate the levels of reactive oxygen species, and regulate the inflammatory microenvironment to inhibit the occurrence of tumors. In addition, curcumin can inhibite the proliferation of tumor cells and promote apoptosis of tumor cells. Here, the paper reviews the mechanism of action of curcumin in cancer prevention and treatment and the new progress in the clinical trials, aiming to provide a basis for research in related fields. Key words: Curcumin; Antineopiastic drugs (TCD); Chemoprevention; Research progress; Review

Isoliquiritigenin inhibits the proliferation, apoptosis and migration of osteosarcoma cells

The overall survival rate of patients with osteosarcoma has remained unchanged for the last several decades. Therefore, novel drugs for osteosarcoma treatment are required. Isoliquiritigenin (ISL), a natural compound, has been demonstrated to inhibit the growth of various tumors. However, it is unclear whether ISL is able to inhibit the growth of osteosarcoma. In the present study, it was identified that ISL was able to inhibit the growth of the osteosarcoma cell line Saos‑2 cells in vitro and in xenograft tumors primarily by attenuating tumor cell proliferation and, cell migration and promoting tumor cell apoptosis. Decreased tumor cell proliferation induced by ISL was associated with downregulation of cyclin D1 and upregulation of p53, p21 and p27. Increased tumor cell apoptosis triggered by ISL was associated with downregulation of apoptosis regulator Bcl‑2, upregulation of apoptosis regulator Bax and damaged mitochondrial function evidenced by a low level of ATP‑synthesis. In addition, ISL was able to inhibit the migratory capacity of Saos‑2 cells by modulating the expression of matrix metalloproteinase (MMP)2 and MMP9. Mechanistic analysis revealed that the tumor growth‑inhibitory effect of ISL may depend on the action of ISL on the phosphorylation of PI3K and AKT. However, it remains to be investigated whether the inhibitory effect of ISL on the migration of Saos‑2 cells was associated with downregulated PI3K/AKT signaling. Overall, the present study provided evidence for the potential use of ISL against osteosarcoma.

Knockdown of RNF2 enhances the radiosensitivity of squamous cell carcinoma in lung.

A previous study has reported that knockdown of RING finger protein 2 (RNF2) increases the radiosensitivity of esophageal cancer cells both in vitro and in vivo. However, the effect of RNF2 knockdown on radiosensitivity in squamous cell carcinoma (SqCC) remains unknown. For this, NCI-H226 and SK-MES-1 cells were exposed to X-ray irradiation and then RNF2 levels were determined. RNF2 was knocked-down and stable transfectants were selected. Radiosensitivity, cell proliferation, apoptosis, cell cycle, and γ-H2AX foci formation were evaluated. Interaction among ataxia telangiectasia mutated protein (ATM), mediator of DNA damage checkpoint 1 (MDC1), and H2AX were examined. Xenograft models were used to explore the effect of RNF2 knockdown on radiosensitivity in vivo. The results showed that RNF2 expression was significantly increased by X-ray irradiation. RNF2 knockdown combined with X-ray irradiation markedly inhibited cell proliferation, caused cell cycle arrest at the G1 phase, and induced cell apoptosis. In addition, RNF2 knockdown enhanced the radiosensitivity of SqCC cells, inhibited irradiation-induced γ-H2AX foci formation, and impaired the interactions among ATM, MDC1, and H2AX. Furthermore, combination of RNF2 knockdown and X-ray irradiation suppressed tumor growth and promoted tumor cell apoptosis in vivo. RNF2 may be a new therapeutic target to enhance the radiosensitivity of SqCC cells in lung.

Anti-tumor activity of a recombinant endoglin-MIP3α Fc-fusion protein in mice with hepatocellular carcinoma

Objective: To investigate the effects of a recombinant endoglin-macrophage inflammatory protein 3α Fc-fusion protein (EM) vaccine on tumor angiogenesis and growth in mice with H22 hepatocellular carcinoma. Methods: An in vivo hepatoma mouse model was established. Seven days after subcutaneous inoculation of H22 tumor cells, mice were randomly divided into four groups: EM, endoglin Fc-fusion protein, macrophage inflammatory protein 3α Fc-fusion protein, and normal saline groups. Tumor volume and survival rate of mice were studied at 3-day intervals. Microvessel density of the tumors and tumor cell proliferation were detected by immunohistochemistry, and tumor cell apoptosis was detected by TdT-mediated biotinylated-dUTP nick-end label staining. The number of CD11c and CD86 positive dendritic cells were detected by flow cytometry. Results: Compared with the other groups, the tumor volume became smaller, and the survival time was longer in the EM-treated group. Besides, microvessel density and cell proliferation index were significantly lower, while the tumor cell apoptosis index was significantly higher in the EM-treated group. Besides the number of CD11c and CD86 positive dendritic cells in EM- treated mice was larger than that in other groups. Conclusions: EM Fc-fusion protein could effectively inhibit tumor growth through inhibiting endoglin-related tumor angiogenesis and cell proliferation, promoting tumor cell apoptosis, and could induce a certain degree of antitumor immune responses.

Citron kinase (CIT-K) promotes aggressiveness and tumorigenesis of breast cancer cells in vitro and in vivo: preliminary study of the underlying mechanism

ObjectivesCitron kinase (CIT-K), as a key Rho effector, functions to maintain proper structure of the midbody during cell mitosis. This study assessed CIT-K expression and its role in breast cancer cells.MethodsParaffin-embedded breast cancer and para-tumor tissues from 43 invasive breast cancer patients and 33 normal mammary glands were collected for immunohistochemistry. CIT-K expression knockdown was achieved using lentivirus carrying CIT-K shRNA in a wide range of breast cancer cell lines. Cells were then subjected to Western blot, qRT-PCR, cell proliferation, colony formation, transwell, and flow cytometric assays. The tumorigenicity of CIT-K knocked-down breast cancer cells was assessed using the nude mouse xenograft assay. Microarray analysis was performed to elucidate the underlying gene regulation after CIT-K silencing.ResultsCIT-K protein was overexpressed in breast cancer tissues, which is associated with advanced tumor stage, HER-2 expression and Ki-67 expression, whereas knockdown of CIT-K expression reduced breast cancer cell proliferation and colony formation, but promoted tumor cell apoptosis and cell-cycle arrest. Knockdown of CIT-K expression also inhibited breast cancer cell migration and invasion capacity. Moreover, CIT-K knockdown suppressed the tumorigenicity of breast cancer cells in nude mice. Molecularly, the expression of a variety of signaling genes, such as cyclin D1, EGFR, JAK1, TGF-α, PTK2, RAF1, RALB, SOS1, mTOR, and PTGS2, were altered after CIT-K knockdown.ConclusionsThis study demonstrated that CIT-K is associated with aggressive breast cancer behavior and targeting CIT-K may be a novel strategy for the future control of breast cancer.

Anti-lung cancer mechanisms of diterpenoid tanshinone via endoplasmic reticulum stress-mediated apoptosis signal pathway

At present, lung cancer ranks second and first respectively in the incidence and the mortality among malignant tumors. It is urgent to find new effective anti-lung cancer drugs with less side effects and relatively defined mechanisms. Endoplasmic reticulum stress (ERS)-mediated apoptosis pathway is an effective way to promote tumor cell apoptosis; diterpenoid tanshinone (DT), an effective part separated from Salviae Miltiorrhizae Radix et Rhizoma, was found to have an anti-lung cancer effect in previous studies via ERS-induced PERK-EIF2α pathway. In this paper, human lung adenocarcinoma PC9 cell line and nude mouse transplantation tumor model were applied to verify the anti-lung cancer effect of DT in vivo and in vitro, and illuminate the potential mechanism via ERS induced IRE1α/caspase 12 apoptosis pathway. The results showed that in vivo, DT could promote PC9 cell apoptosis in a concentration-dependent manner, up-regulate Bip, IRE1 and TRAF2 protein expressions in tumor tissue, reduce tumor weight and alleviate bodyweight loss. In vitro, DT inhibited the proliferation of PC9 cell line in a concentration-dependent manner, and destroyed the structure of mitochondria in PC9 cell, promoted Bax, IRE1α, Bip, TRAF2 and caspase 12 protein expressions, lower Bcl-2 protein expression in a time-dependent manner. DT shows a good effect on anti-lung cancer both in vivo and in vitro. The mechanism is related to the activation of ERS-induced IRE1α/caspase 12 apoptosis pathway and the promotion of cell apoptosis. ERS-mediated apoptosis pathway may be an important target of DT on anti-lung cancer.

The research on the mechanism of Tsoong inhibiting for colon cancer.

The roots of Codonopis bulleynana Forest ex diels (cbFed), locally known as Tsoong, have been used as a tonic food. Tsoong has wide range of pharmacological effects, including anticancer effects. In the present study, the anticancer activity of Tsoong and its potential molecular mechanisms were investigated. Using high throughput sequencing the apoptotic pathway was ranked as one of the most important pathways and the differential expressions of apoptosis-related genes such as Casp3, Casp6 and Apaf1 were identified. The following experiments were qRT-PCR which were used to verify the genes. In vitro, cell counting kit-8 (CCK-8) assays and flow cytometry in HCT116 and SW480 colon cancer cell were used to assess the anti‐proliferation and apoptosis-promoting activities of Tsoong. In vivo, the antitumor effect of Tsoong was assessed in colon cancer-bearing nude mice as a xenograft model. H&E staining was performed with oxaliplatin set as a positive control. The results showed that Tsoong up-regulated apoptosis-related genes, inhibited tumor cell proliferation, promoted tumor cellapoptosis in a dose-dependent manner and restrained the growth of colon neoplasm. The effects of a high dose of Tsoong on colon cancer cells were similar to those of oxaliplatin. Our results may ultimately help in the development of diagnostic and therapeutic strategies to control this devastating disease. Therefore, Tsoong may be a promising Chinese herbal compound for development for use in cancer therapy.

Effect of long non-coding RNA highly upregulated in liver cancer on the biological behavior of oral squamous cell carcinoma

Objective: To investigate the effect of long non-coding RNA highly upregulated in liver cancer (lncRNA HULC) on the biological behavior of oral squamous cell carcinoma (OSCC) cell lines. Methods: A total of thirty patients with oral squamous cell carcinoma at Peking University Shenzhen Hospital from March 2017 to March 2018 were enrolled in this study. OSCC and adjacent tissues were extracted during tumor extensive resection. Quantitative real-time PCR (qPCR) was used to detect the expression levels of lncRNA HULC in OSCC and paracancerous tissues and OSCC cell lines. SCC15 and SCC25 cells were transfected with siRNA, and the effects of the gene on the biological behavior of OSCC cells were detected by cell counting assay, scratch assay, Transwell assay and Western blotting. Results: The expression of lncRNA HULC in OSCC tissues (10.98±0.31, n=30) was significantly higher than that in paracancerous tissues (8.39±0.31, n=30) (t=5.93, P<0.001), the expression of lncRNA HULC in OSCC cells (SCC15: 28.58±2.74; SCC25: 16.56±0.87; SCC9: 11.18±1.32; CAL27: 13.92±0.99, n=5) was significantly higher than that in human keratinocytes (1.01±0.00, n=5) (t(SCC15)=10.08, t(SCC25)=17.96, t(SCC9)=7.71, t(CAL27)=13.09, P<0.001). Down-regulation of lncRNA HULC in SCC15 and SCC25 cells can inhibit the proliferation, migration and invasion of tumor cells and promote tumor cell apoptosis. Conclusions: lncRNA HULC is highly expressed in OSCC and can enhance the proliferation, migration and invasion of cancer cells and inhibit tumor cell apoptosis.

Effects of forkhead Box protein A1 on cell proliferation regulating and EMT of cervical carcinoma.

Cervical cancer is a common tumor in gynecological malignancies. However, the patients are often in an advanced stage when diagnosed. It was found that forkhead box protein A1 (FOXA1) is abnormally expressed in various tumors, such as breast cancer, ovarian cancer, and is closely related to tumorigenesis. This study aimed to investigate the expression and the related roles of FOXA1 in cervical cancer. Real Time-PCR (RT-PCR) and Western blot were used to analyze expression of FOXA1 in cervical cancer and adjacent tissue. The small-interfere RNA (siRNA) was adopted to down-regulate FOXA1 expression in HeLa cells. The effect of FOXA1 on apoptosis of HeLa cells was detected by using thiazolyl blue tetrazolium bromide (MTT) method. The apoptosis rate of HeLa cells was detected by using flow cytometry. The Western blot was selected to evaluate the epithelial mesenchymal transition (EMT) related protein, vimentin, E-cadherin, and vascular endothelial growth factor (VEGF) changes. Compared with adjacent tissues, FOXA1 mRNA and protein expressions significantly increased in cervical cancer (p<0.05). SiRNA significantly reduced FOXA1 expression in Hela cells compared with the control group and siRNA-NC group, thus inhibiting tumor cell proliferation and enhancing cell apoptosis rate (p<0.05). E-cadherin elevated, Vimentin decreased, and VEGF reduced after FOXA1 siRNA treatment. FOXA1 expression increased in cervical cancer. Inhibition of FOXA1 expression blocked the proliferation of cervical cancer, promoted tumor cell apoptosis, suppressed the occurrence of EMT and VEGF production, and can regulate cervical cancer metastasis. FOXA1 can be used as a new molecular biological target for cervical cancer diagnosis and treatment.

Foxf2 plays a dual role during transforming growth factor beta-induced epithelial to mesenchymal transition by promoting apoptosis yet enabling cell junction dissolution and migration

BackgroundThe most life-threatening step during malignant tumor progression is reached when cancer cells leave the primary tumor mass and seed metastasis in distant organs. To infiltrate the surrounding tissue and disseminate throughout the body, single motile tumor cells leave the tumor mass by breaking down cell-cell contacts in a process called epithelial to mesenchymal transition (EMT). An EMT is a complex molecular and cellular program enabling epithelial cells to abandon their differentiated phenotype, including cell-cell adhesion and cell polarity, and to acquire mesenchymal features and invasive properties.MethodsWe employed gene expression profiling and functional experiments to study transcriptional control of transforming growth factor (TGF)β-induced EMT in normal murine mammary gland epithelial (NMuMG) cells.ResultsWe identified that expression of the transcription factor forkhead box protein F2 (Foxf2) is upregulated during the EMT process. Although it is not required to gain mesenchymal markers, Foxf2 is essential for the disruption of cell junctions and the downregulation of epithelial markers in NMuMG cells treated with TGFβ. Foxf2 is critical for the downregulation of E-cadherin by promoting the expression of the transcriptional repressors of E-cadherin, Zeb1 and Zeb2, while repressing expression of the epithelial maintenance factor Id2 and miRNA 200 family members. Moreover, Foxf2 is required for TGFβ-mediated apoptosis during EMT by the transcriptional activation of the proapoptotic BH3-only protein Noxa and by the negative regulation of epidermal growth factor receptor (EGFR)-mediated survival signaling through direct repression of its ligands betacellulin and amphiregulin. The dual function of Foxf2 during EMT is underscored by the finding that high Foxf2 expression correlates with good prognosis in patients with early noninvasive stages of breast cancer, but with poor prognosis in advanced breast cancer.ConclusionsOur data identify the transcription factor Foxf2 as one of the important regulators of EMT, displaying a dual function in promoting tumor cell apoptosis as well as tumor cell migration.

Short Call Abstracts

Short Call Abstracts

Shikonin Inhibits Tumor Growth in Mice by Suppressing Pyruvate Kinase M2-mediated Aerobic Glycolysis

Shift metabolism profile from mitochondrial oxidative phosphorylation to aerobic glycolysis (Warburg effect) is a key for tumor cell growth and metastasis. Therefore, suppressing the tumor aerobic glycolysis shows a great promise in anti-tumor therapy. In the present study, we study the role of shikonin, a naphthoquinone isolated from the traditional Chinese medicine Lithospermum, in inhibiting tumor aerobic glycolysis and thus tumor growth. We found that shikonin dose-dependently inhibited glucose uptake and lactate production in Lewis lung carcinoma (LLC) and B16 melanoma cells, confirming the inhibitory effect of shikonin on tumor aerobic glycolysis. Treatment of shikonin also decreased tumor cell ATP production. Furthermore, pyruvate kinase M2 (PKM2) inhibitor or activator respectively altered the effect of shikonin on tumor cell aerobic glycolysis, suggesting that suppression of cell aerobic glycolysis by shikonin is through decreasing PKM2 activity. Western blot analysis confirmed that shikonin treatment reduced tumor cell PKM2 phosphorylation though did not reduce total cellular PKM2 level. In vitro assay also showed that shikonin treatment significantly promoted tumor cell apoptosis compared to untreated control cells. Finally, when mice implanted with B16 cells were administered with shikonin or control vehicle, only shikonin treatment significantly decreased B16 tumor cell growth. In conclusion, this study demonstrates that shikonin inhibits tumor growth in mice by suppressing PKM2-mediated aerobic glycolysis.

Antitumor effects of the silencing of programmed cell death ligand1 in colorectal cancer via immunoregulation.

Activation of programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) can promote immune suppression of the tumor microenvironment. However, the effects and mechanisms of PD-L1 silencing on colorectal cancer growth are largely unknown. In the present study, PD-L1 expression was compared in colorectal cancer and paracancerous tissues by immunofluorescence. A stable colorectal carcinoma cell line encoding PD-L1 short hairpin RNA (shRNA) was established. Thereafter, inoculated tumors were modeled in C57B/L6 mice. Experiments were divided into 3 groups: Control group, vector group, and PD-L1 silencing group (inoculated with the stable CT26 cell line encoding PD-L1 shRNA). Following decapitation of the mice, tumors were weighed and apoptosis of tumor cells was detected. The number and viability of cluster of differentiation (CD)4+ and CD8+ T cells were analyzed by flow cytometry and a cell counting kit assay, respectively. Compared with paracancerous tissue, colorectal cancer tissue extensively expressed PD-L1, RAC-α serine/threonine-protein kinase (AKT), and phosphatidylinositol 3-kinase (PI3K). Lymphocyte-activating gene 3 (LAG-3) expression was observed at the edge of tumor tissue, but rarely observed in paracancerous tissue. A stable CT26 cell line encoding PD-L1 shRNA was established, and lack of PD-L1 expression was confirmed by reverse transcription-polymerase chain reaction and western blotting. Compared with the control, the shPD-L1 group demonstrated reduced tumor growth, a high level of apoptosis in tumor cells, a low level of PI3K and AKT expression, and an increased number of cells and greater activity of CD4+ T and CD8+ T cells. Taken together, PD-L1 silencing promoted tumor cell apoptosis, at least in part, through the activation of CD4+ and CD8+ T cells.

Hyaluronan Reduces Cationic Liposome-Induced Toxicity and Enhances the Antitumor Effect of Targeted Gene Delivery in Mice.

Cationic nanocarriers are reported to induce cell necrosis, especially in the lungs upon systemic administration. The release of damage-associated molecular patterns, such as mitochondrial DNA from the injured cell may result in the inflammatory toxicity of the nanocarrier, which has largely limited its clinical application. Partial blocking of the surface charge of cationic nanocarriers might improve their safety. As hyaluronan (HA) is an anionic polysaccharide that is widely used for specific binding to CD44 to improve the cellular uptake efficiency in tumor-targeting therapy, in this study, we modified cationic liposomes (LP) with the negatively charged HA at a mass ratio of 10% to prepare targeted HA-modified cationic liposomes (HALP). Cationic liposomes modified with hyaluronan showed significantly less cytotoxicity due to the blockage of their surface charge than the unmodified liposomes. In addition, HA modification helped to reduce cell necrosis in lung tissue and reduced the amount of mitochondria subsequently released, which alleviated pulmonary inflammation in mice. HA-modified liposomes also improved the survival of mice injected with a fatal dose of HALP compared with mice injected with cationic LP. In addition, both serological biochemical analysis and histological examination proved that a liposome modified with HA is a safer carrier for systemic administration than an unmodified liposome. Furthermore, HALP/survivin exhibited an enhanced antitumor effect by inhibiting tumor growth and promoting tumor cell apoptosis compared with the unmodified LP group. In conclusion, compared to the properties of cationic liposomes, liposomes modified with 10% HA (HALP) might be gene vectors with lower toxicity and higher tumor targeting efficiency.

In vitro effects of PI3K/mTOR inhibition in canine hemangiosarcoma

While extremely rare in humans, hemangiosarcoma (HSA) accounts for nearly 2% of canine neoplasia, and is characterized by both aggressive local growth/invasion and a high rate of metastasis. Both canine and human HSA exhibit sustained aberrant PI3K/Akt/mTOR pathway signaling. The purpose of this study was to examine the in vitro effects of a novel dual PI3K/mTOR inhibitor, VDC-597, in three canine HSA cell lines (DEN-, CIN-, and SB-HSA). VDC-597 suppressed activation of both Akt and 4eBP1 in canine HSA cells in a dose-dependent fashion, with an IC50 of approximately 0.3 uM, a concentration predicted to be clinically achievable based on preliminary early-phase canine and human studies. VDC-597 dose-dependently reduced proliferation, migration, and vascular endothelial growth factor production in HSA cells, while promoting tumor cell apoptosis. VDC-597 demonstrated additive antiproliferative effects when combined with doxorubicin. These results suggest that inhibitors of the PI3K/mTOR pathway may act against multiple components of the neoplastic process, including proliferation/apoptosis, chemosensitivity, migration, and angiogenesis, and justify the evaluation of PI3K/mTOR inhibitors in canine, and potentially human, HSA.

Effect of As2O3 on colorectal CSCs stained with ALDH1 in primary cell culture in vitro.

Colorectal carcinoma (CRC) is one of the most common types of malignant tumor in humans, and its morbidity is on the increase in economically transitioning countries. Due to its high toxicity, the use of the Chinese Traditional Medicine arsenic (As2O3) is limited. However, certain studies have reported that As2O3 induces differentiation of tumor cells, promotes tumor cell apoptosis and inhibits tumor cell proliferation, although the number of studies on the effects of As2O3 on cancer stem cells (CSCs) of CRC is limited. In order to research the effects of different concentrations of As2O3 on CRC cells and colorectal CSCs in vitro, aldehyde dehydrogenase 1 (ALDH1) was sued to stain the cytoplasm of colorectal CSCs and DAPI was used to stain the nuclei of all tumor cells. Through observing the effect of different concentrations of As2O3 on CRC cells and colorectal CSCs, it was demonstrated that a sufficient concentration of As2O3 clearly inhibited the conversion from colorectal CSCs to CRC cells and increased the density of CSCs.

Roles of physical therapies in chemosensitization of non-small cell lung cancer

Chemotherapy is an important treatment of non-small cell lung cancer (NSCLC), the efficiency of chemotherapy directly affects the survival rate and living quality of patients. Studies show that physical therapies such as hyperthermia, tumor treating fields, alternating micro-current, hyperbaric oxygen treatment and photodynamic therapy play chemosensitization effects in NSCLC by means of improving the concentrations of chemotherapeutic agents in tumor cells, promoting tumor cell apoptosis, inhibiting the expressions of multidrug resistance gene and protein and other ways. Key words: Carcinoma, non-small-cell lung; Physical therapy modalities; Chemosensitization

Decreased expression level and DNA-binding activity of specificity protein 1 via cyclooxygenase-2 inhibition antagonizes radiation resistance, cell migration and invasion in radiation-resistant lung cancer cells.

Radiation is able to inhibit tumor growth, promote tumor cell apoptosis and prolong patient survival. However, radiation resistance remains a major impediment to radiotherapy. Local and metastatic recurrences following radiation are still large impediments to overall survival. Although cyclooxygenase-2 (COX-2) inhibitors may induce radiation sensitivity in cancer cells, the underlying mechanisms are not fully understood. The present study demonstrated high potential for cell proliferation, migration and invasion in radiation-resistant lung cancer cell lines. The present study observed the overexpression of specificity protein 1 (Sp1) in these cells, and the overexpression of Sp1 induced upregulation of matrix metalloproteinase (MMP)-2, MMP-9, B cell lymphoma-2, in addition to a high potential for radiation resistance, migration and invasion in these cells. The present study revealed that the COX-2 selective inhibitor, celecoxib, enhanced radiation sensitivity and inhibited migration and invasion in these cells by inhibiting the expression and DNA-binding activity of Sp1. Furthermore, celecoxib downregulated Sp1 by inhibiting c-Jun N-terminal kinase (JNK). Taken together, the present study demonstrated that Sp1 overexpression in radiation-resistant cancer cells and COX-2 inhibitors enhanced radiation sensitivity and inhibited the migration and invasion of cancer cells, at least partially, via inactivation of the JNK/Sp1 signaling pathway and a decrease in Sp1 DNA-binding activity.