Transcatheter arterial chemoembolization plus apatinib with or without camrelizumab for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study.

BACKGROUND: The evidence of transcatheter arterial chemoembolization (TACE) plus tyrosine kinase inhibitor and immune checkpoint inhibitor in unresectable hepatocellular carcinoma (HCC) was limited. This study aimed to evaluate the role of TACE plus apatinib (TACE + A) and TACE combined with apatinib plus camrelizumab (TACE + AC) in patients with unresectable HCC. METHODS: This study retrospectively reviewed patients with unresectable HCC who received TACE + A or TACE + AC in 20 centers of China from January 1, 2019 to June 31, 2021. Propensity score matching (PSM) at 1:1 was performed to reduce bias. Treatment-related adverse events (TRAEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were collected. RESULTS: A total of 960 eligible patients with HCC were included in the final analysis. After PSM, there were 449 patients in each group, and the baseline characteristics were balanced between two groups. At data cutoff, the median follow-up time was 16.3 (range: 11.9-21.4) months. After PSM, the TACE + AC group showed longer median OS (24.5 vs 18.0 months, p < 0.001) and PFS (10.8 vs 7.7 months, p < 0.001) than the TACE + A group; the ORR (49.9% vs 42.5%, p = 0.002) and DCR (88.4% vs 84.0%, p = 0.003) of the TACE + AC group were also higher than those in the TACE + A group. Fever, pain, hypertension and hand-foot syndrome were the more common TRAEs in two groups. CONCLUSIONS: Both TACE plus apatinib and TACE combined with apatinib plus camrelizumab were feasible in patients with unresectable HCC, with manageable safety profiles. Moreover, TACE combined with apatinib plus camrelizumab showed additional benefit.

Oxidative C-H/N-H Carbonylation of Benzamide by Nickel Catalysis with CO as the Carbonyl Source.

An efficient and direct carbonylation of aminoquinoline benzamides has been developed using abundant and inexpensive Ni(OAc)2·4H2O as the catalyst and carbon monoxide as a cost-efficient C1 building block. This process features good functional-group tolerance and can be conducted on gram scale. The directing group can be easily removed under mild conditions.

Copper-Catalyzed Divergent C-H Functionalization Reaction of Quinoxalin-2(1H)-ones and Alkynes Controlled by N1-Substituents for the Synthesis of (Z)-Enaminones and Furo[2,3-b]quinoxalines.

With control by N1-substituents, the switchable divergent C-H functionalization reaction of quinoxalin-2(1H)-ones is achieved for the synthesis of (Z)-enaminones and furo[2,3-b]quinoxalines using the combination of a copper catalyst and an oxidant. This new protocol features mild reaction conditions, readily available materials, and a broad substrate scope. Gram-scale and mechanistic studies were also investigated. Furthermore, the desired products exhibited excellent antitumor activity against A549, HepG-2, MCF-7, and HeLa cells, which were tested by MTT assay.

Systematic evaluation of the antitumor activity of three ruthenium polypyridyl complexes.

Ruthenium-containing complexes have emerged as good alternative to the currently used platinum-containing drugs for malignant tumor therapy. In this work, cytotoxic effects of recently synthesized ruthenium polypyridyl complexes [Ru(bpy)2(CFPIP)](ClO4)2 (bpy = 2,2'-bipyridine, CFPIP = (E)-2-(4-fluorostyryl)-1H-imidazo[4,5-f][1,10]phenanthroline, Ru(II)-1), [Ru(phen)2(CFPIP)](ClO4)2 (phen = 1,10-phenanthroline, Ru(II)-2) and [Ru(dmb)2(CFPIP)](ClO4)2 (dmb = 4,4'-dimethyl-2,2'-bipyridine, Ru(II)-3) toward different tumor cells were investigated in vitro and compared with cisplatin, the most widely used chemotherapeutic drug against hepatocellular carcinoma (HepG-2). The results demonstrate that target complexes show excellent cytotoxicity against HepG-2 cells with low IC50 value of 21.4 ± 1.5, 18.0 ± 2.1 and 22.3 ± 1.7 µM, respectively. It was important noting that target Ru(II) complexes exhibited better antitumor activity than cisplatin (IC50 = 28.5 ± 2.4 µM) against HepG-2 cells, and has no obvious toxicity to normal cell LO2. DNA binding results suggest that Ru(II)-1, Ru(II)-2 and Ru(II)-3 interact with CT DNA (calf thymus DNA) through intercalative mode. Complexes exerted its antitumor activity through increasing anti-migration and inducing cell cycle arrest at the S phase. In addition, the apoptosis was tested by AO (acridine orange)/EB (ethidium bromide) staining and flow cytometry. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and colocalization tests were also evaluated by ImageXpress Micro XLS system. Overall, the results show that the ruthenium polypyridyl complexes induce apoptosis in HepG-2 cells through ROS-mediated mitochondria dysfunction pathway.

Association Between the Aldehyde Dehydrogenase-2 rs671 G>A Polymorphism and Head and Neck Cancer Susceptibility: A Meta-Analysis in East Asians.

BACKGROUND: Aldehyde dehydrogenase-2 (ALDH2) plays an important role in the alcohol detoxification and acetaldehyde metabolism. Published studies have demonstrated some inconsistent associations between ALDH2 rs671 G>A polymorphism and head and neck cancer (HNC) risk. METHODS: A meta-analysis was performed to provide pooled data on the association between the ALDH2 rs671 G>A polymorphism and HNC risk. Electronic databases were searched to identify relevant studies. Odds ratios and 95% confidence intervals (CIs) were used to examine the pooled effect size of each genetic model. In addition, heterogeneity test, accumulative analysis, sensitivity analysis, and publication bias were conducted to test the statistical power. RESULTS: Thirteen publications (14 independent case-control studies) involving 10,939 subjects were selected. The stratified analysis indicated that both light/moderated drinking (e.g., GA vs. GG: OR = 1.47, 95% CI = 1.16 to 1.86, p < 0.01, I2  = 81.1%) and heavy drinking would increase HNC risk with rs671 G>A mutation (e.g., GA vs. GG: OR = 2.30, 95% CI = 1.11 to 4.77, p = 0.03, I2  = 81.9%). CONCLUSIONS: In summary, this meta-analysis suggested that the ALDH2 rs671 G>A polymorphism may play an important synergistic effect in the pathogenesis of HNC development in East Asians.

Association between the pri-miR-26a-1 rs7372209 C>T polymorphism and cancer susceptibility: multivariate analysis and trial sequential analysis.

MiR-26 has been suggested to play a tumor-suppressive role in cancer development, which could be influenced by the mutate pri-miR-26ª-1. Molecular epidemiological studies have demonstrated some inconsistent associations between pri-miR-26ª-1 rs7372209 C>T polymorphism and cancer risk. We therefore performed this meta-analysis with multivariate statistic method to comprehensively evaluate the associations between rs7372209 C>T polymorphism and cancer risk. Eleven publications involving 6,709 patients and 6,514 controls were identified. Multivariate analysis indicated that the over-dominant genetic model was most likely. Pooled results indicated no significant association in the overall population (CC+TT vs. CT: OR=1.08, 95%CI=0.96-1.22, P=0.20, I2=54.4%), as well as the subgroup analysis according to ethnicity, control source, tumor locations, and HWE status of controls. In addition, heterogeneity, accumulative, sensitivity analysis, publication bias and trial sequential analysis (TSA) were conducted to test the statistical power. Overall, our results indicated that the pri-miR-26a-1 rs7372209 C>T polymorphism may not be a potential risk for cancer development.

Antibacterial activity of ruthenium polypyridyl complexes against Staphylococcus aureus and biofilms.

There is clearly a need for the development of new classes of antimicrobials to fight against multidrug-resistant bacteria. Here, we designed and synthesized of three ruthenium polypyridyl complexes: [Ru(bpy)2(BTPIP)](ClO4)2 (Ru(II)-1), [Ru(bpy)2(ETPIP)](ClO4)2 (Ru(II)-2) and [Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-3) (N-N = bpy = 2,2'-bipyridine), their antimicrobial activities against S. aureus were assessed. The lead complexes of this set, Ru(II)-1(MIC = 0.016 mg/mL), was tested against biofilm. We also investigated whether bacteria can easily develop resistance to Ru(II)-1. The result demonstrated that S. aureus could not easily develop resistance to the ruthenium complexes. In addition, aimed to test whether ruthenium complexes treatment could increase the susceptibility of S. aureus to antibiotics, the synergism between Ru(II)-1 and common antibiotics against S. aureus were investigated using the checkerboard method. Interesting, Ru(II)-1 could increased the susceptibility of S. aureus to some aminoglycoside antibiotics(kanamycin and gentamicin). Finally, in vivo bacterial infection treatment studies were also conducted through murine skin infection model. These results confirmed ruthenium complexes have good antimicrobial activity in vitro and in vivo.

Development of four ruthenium polypyridyl complexes as antitumor agents: Design, biological evaluation and mechanism investigation.

Ruthenium complexes are expected to be new opportunities for the development of antitumor agents. Herein, four ruthenium polypyridyl complexes ([Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-1, bpy = 2,2'-bipyridine; CAPIP = (E)-2-(2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ru(phen)2(CA-PIP)](ClO4)2 (Ru(II)-2, phen = 1,10-phenanthroline), [Ru(dmb)2(CAPIP)](ClO4)2 (Ru(II)-3, dmb = 4,4'-dimethyl-2,2'-bipyridine), [Ru(dmb)2(ETPIP)](ClO4)2 (Ru(II)-4, ETPIP = 2-(4-(thiophen-2-ylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phen-anthroline)) have been investigated as mitochondria-targeted antitumor metallodrugs. DNA binding studies indicated that target Ru(II) complexes interacts with CT DNA (calf thymus DNA) by an intercalative mode. Cytotoxicity assay results demonstrate that Ru(II) complexes show high cytotoxicity against A549 cells with low IC50 value of 23.6 ± 2.3, 20.1 ± 1.9, 22.7 ± 1.8 and 18.4 ± 2.3 µM, respectively. Flow cytometry and morphological analysis revealed that these Ru(II) complexes can induce apoptosis in A549 cells. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were also investigated by ImageXpress Micro XLS system. The experimental results indicate that the reactive oxygen species in A549 cells increased significantly and mitochondrial membrane potential decreased obviously. In addition, colocalization studies shown these complexes could get to the cytoplasm through the cell membrane and accumulate in the mitochondria. Furthermore, Ru(II) complexes can effectively induces cell cycle arrest at the S phase in A549 cells. Finally, cell invasion assay and quantitative studies were also performed to investigate the mechanism of this process. All in together, this study suggested that these Ru(II) complexes could induce apoptosis in A549 cells through cell cycle arrest and ROS-mediated mitochondrial dysfunction pathway.

New ruthenium polypyridyl complexes functionalized with fluorine atom or furan: Synthesis, DNA-binding, cytotoxicity and antitumor mechanism studies.

Two novel ruthenium(II) polypyridyl complexes, namely, [Ru(dmp)2(CAPIP)](ClO4)2 (Ru(II)-1) and [Ru(dmp)2(CFPIP)](ClO4)2 (Ru(II)-2), which respectively contain (E)-2-(2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phen-anthroline (CAPIP) and (E)-2-(4-fluorostyryl)-1H-imidazo[4,5-f][1,10]phenanthroline. (CFPIP), were first designed and characterized (dmp = 2,9-dimethyl-1,10-phenanthroline). DNA binding experiments indicated that Ru(II) complexes interact with CT DNA through intercalative mode. In addition, the complexes Ru(II)-1 and Ru(II)-2, showed remarkable cell cytotoxicity, giving the respective IC50 values of 4.1 ±â€¯1.4 µM and 6.1 ±â€¯1.4 µM on the A549 cancer cells. These values indicated higher activity than CAPIP, CFPIP, cisplatin (8.2 ±â€¯1.4 µM) and other corresponding Ru(II) polypyridyl complexes. Furthermore, the Ru(II) complexes could arrive the cytoplasm through the cell membrane and accumulate in the mitochondria. Significantly, complexes Ru(II)-1 and Ru(II)-2 induced A549 cells apoptosis was mediated by increase of ROS levels and dysfunction of mitochondria, and resulted in cell cycle arrest and increased anti-migration activity on A549 cells. Overall, these results indicated that complexes Ru(II)-1 and Ru(II)-2 could be suitable candidates for further investigation as a chemotherapeutic agent in the treatment of tumors.

Design and synthesis of new ruthenium polypyridyl complexes with potent antitumor activity in vitro.

We herein report the synthesis, characterization and anticancer activity of BTPIP (2-(4-(benzo[b]thiophen-2-yl)phenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) and its four ruthenium(II) polypyridyl complexes [Ru(NN)2(BTPIP)](ClO4)2 (N-N = bpy = 2,2'-bipyridine, Ru(II)-1; phen = 1,10-phenanthroline, Ru(II)-2; dmb = 4,4'-dimethyl-2,2'-bipyridine, Ru(II)-3; dmp = 2,9-dimethyl-1,10-phenanthroline, Ru(II)-4). The DNA binding behaviors reveal that the complexes bind to calf thymus DNA by intercalation. Cytotoxicity of the complexes against A549, HepG-2, SGC-7901 and Hela cells were evaluated in vitro. Complexes Ru(II)-1, Ru(II)-2, Ru(II)-3, Ru(II)-4 show moderate activity on the cell proliferation in A549 cells with IC50 values of 9.3 ±â€¯1.2, 12.1 ±â€¯1.6, 10.3 ±â€¯1.6, 8.9 ±â€¯1.2 µM, respectively. Apoptosis assessment, intracellular mitochondrial membrane potential (MMP), location in mitochondria, reactive oxygen species (ROS), cell invasion assay and cell cycle arrest were also performed to explore the mechanism of this action. When the concentration of the ruthenium(II) complexes is increased, the amount of reactive oxygen species increases obviously and the mitochondrial membrane potential decreases dramatically in A549 cells. Most importantly, the ruthenium(II) polypyridyl complexes could arrive the cytoplasm through the cell membrane and accumulate in the mitochondria. These results showed that the ruthenium(II) complexes could induce apoptosis in A549 cells through an ROS-mediated mitochondrial dysfunction pathway.

Quantitative assessment of the relationship between Fas/FasL genes polymorphisms and head and neck cancer risk.

BACKGROUND: Molecular epidemiological studies have demonstrated a closer association between Fas/FasL polymorphisms and head and neck cancer (HNC) risk, and the results of these published studies were inconsistent. We therefore performed this meta-analysis to explore the associations between Fas/FasL polymorphisms and HNC risk. METHODS: Four online databases (PubMed, Embase, CNKI, and Wanfang) were searched. Odds ratios (ORs) with 95% confidence interval (95% CIs) were calculated to assess the association between Fas -670A>G, Fas -1377G>A, and FasL -844C>T polymorphisms and HNC risk. In addition, heterogeneity, accumulative/sensitivity analysis, and publication bias were conducted to check the statistical power. RESULTS: Overall, 9 related publications (20 independent case-control studies) involving 3179 patients and 4217 controls were identified. Significant association of protective effects was observed between FasL -844C>T polymorphism and HNC risk in codominant and dominant model models (CT vs CC: OR = 0.89, 95% CI = 0.79-1.00, P = .05, I = 38.3%, CT+TT vs CC: OR = 0.88, 95% CI = 0.79-0.98, P = .02, I = 35.8%). Furthermore, the similar protective effects were observed the subgroup analysis of in Asian population and population-based controls group. CONCLUSION: Our meta-analysis indicated that FasL -844C>T polymorphism plays a protective role against HNC development, but the Fas -670A>G and Fas -1377G>A polymorphisms maybe not associated with HNC risk.

Regulatory role of miR-211-5p in hepatocellular carcinoma metastasis by targeting ZEB2.

Hepatocellular carcinoma (HCC) is the most common type of cancer and the rapid tumor growth, drug resistance and metastasis are the major problems for HCC therapy. MicroRNAs (miRNAs) involve in various cell biological processes in HCC. ZEB2 plays crucial roles in HCC progression. ZEB2 is regulated by some identified miRNAs, but there needs to find new miRNAs regulating ZEB2 expression for better understanding the molecular mechanism of HCC. In the present study, ZEB2 was identified as a direct target of miR-211-5p, which was a potential oncogene in cancer. We found that miR-211-5p levels in HCC tissues were lower than the compared normal tissues. ZEB2 expression was higher in HCC tissues and was negatively related to miR-211-5p levels. Overexpression of miR-211-5p in human HCC cell lines (HepG2 and 7721) caused the delay of cell proliferation, apoptosis and drug sensitivity. Summarily, our study demonstrates that miR-211-5p may play a suppressing role in HCC by inhibiting ZEB2 expression.

[GenomeLabTM GeXP analysis system to detect apoptosis-associated genes in A549 cells treated by recombinant human IL-24 combined with cisplatin].

Objective To investigate the changes of apoptosis-associated genes in human lung adenocarcinoma cell line A549 after treated by the recombinant human interleukin-24 (rhIL-24) combined with cisplatin (DDP). Methods The mRNA levels of Bax, Bcl-2, survivin, caspase-3, retinoblastoma (Rb) gene, p53 were analyzed by GenomeLabTM GeXP genetic analysis system after A549 cells were treated with 160 ng/mL rhIL-24 or 3 µg/mL DDP or 160 ng/mL rhIL-24 combined with 3 µg/mL DDP. Results The rhIL-24 up-regulated the levels of Bax, Rb, caspase-3 mRNAs and down-regulated Bcl-2, survivin mRNAs, but the change of p53 mRNA was not regular. The combination of rhIL-24 and DDP strengthened the above changes. Conclusion The rhIL-24 protein can induce the apoptosis of A549 cells by up-regulating Bax, caspase-3, Rb mRNAs and down-regulating Bcl-2, survivin mRNAs.

miR-204-5p targeting SIRT1 regulates hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is the most common type of cancer, which presents rapid tumor growth, drug resistance, and metastasis. Recently, microRNAs are shown to be involved in the cell biological processes in HCC, but the underlying molecular mechanisms remain unclear. This study aimed to investigate the cellular function and molecular mechanism of miR-204-5p in HCC. SIRT1 mRNA and miR-204-5p were examined by real-time reverse transcription polymerase chain reaction. SIRT1 protein levels were measured by Western blotting. Cell proliferation assay was performed to confirm colony formation. Invasion assay was performed by transwell system. SPSS 15.0 for Windows was used for statistical analysis. SIRT1 was a potential oncogene in cancer, which was identified as a direct target of miR-204-5p. Overexpression of miR-204-5p in human HCC cell lines (BEL-7405 and QGY-7701) caused the suppression of cell survival ability, the increase of apoptosis, and drug sensitivity. SIRT1 was overexpressed in human HCC tissues and was negatively related to miR-204-5p levels. These results indicate that miR-204-5p and SIRT1 may play an important role in the development of HCC.

Synthesis, characterization and anticancer activity studies of ruthenium(II) polypyridyl complexes on A549 cells.

Four new ruthenium(II) polypyridyl complexes [Ru(N-N)2(bddp)](ClO4)21-4 (N-N=dmb: 4,4'-dimethyl-2,2'-bipyridine 1, bpy: 2,2'-bipyridine 2, phen: 1,10-phenanthroline 3 and dmp: 2,9-dimethyl-1,10-phenanthroline 4, bddp=benzilo[2,3-b]-1,4-diazabenzo[i]dipyrido[3,2-a:2',3'-c]phenazine) were synthesized and characterized by elemental analysis, ESI-MS and (1)H NMR. The cytotoxicity in vitro of the complexes against BEL-7402, HeLa, MG-63 and A549 cell lines was investigated by MTT method. The complexes show high cytotoxic activity toward the selected cell lines with an IC50 value ranging from 5.3±0.6 to 15.7±3.6µM. The apoptosis was studied with acridine orange (AO)/ethdium bromide (EB) and Hoechst 33258 staining methods. The cellular uptake was investigated with DAPI staining method. The reactive oxygen species (ROS) and mitochondrial membrane potential were performed under fluorescent microscope and flow cytometry. The complexes can induce an increase in the ROS levels and a decrease in the mitochondrial membrane potential. The comet assay was studied with fluorescent microscope. The percentage in apoptotic and necrotic cells and cell cycle arrest were assayed by flow cytometry. The effects of the complexes on the expression of caspases and Bcl-2 family proteins were studied by western blot analysis. The results show that the complexes induce apoptosis in A549 cells through an ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulating the expression of Bcl-2 family proteins.

Protein binding and anticancer activity studies of ruthenium(II) polypyridyl complexes toward BEL-7402 cells.

Four new ruthenium(II) polypyridyl complexes [Ru(dmb)2(dqtbt)](ClO4)2 (1) (dqtbt=12-(2,3-diphenyl-quinoxalin-6-yl)-4,5,10,13-tetraazabenzo[b]triphenylene, dmb=4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)2(dqtbt)](ClO4)2 (2) (bpy=2,2'-bipyridine), [Ru(phen)2(dqtbt)](ClO4)2 (3) (phen=1,10-phenanthroline) and [Ru(dmp)2(dqtbt)](ClO4)2 (4) (dmp=2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized. The cytotoxicity in vitro of the complexes was evaluated against human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines. These complexes are sensitive to BEL-7402 cells, the IC50 values are 4.9±0.5, 4.6±0.4, 7.7±1.8 and 1.9±0.3µM toward BEL-7402 cells. The complexes can increase the levels of reactive oxygen species and induce the decrease of mitochondrial membrane potential. Morphological and comet assay studies show that the complexes can effectively induce apoptosis in BEL-7402 cells. Complexes 1-4 inhibit the cell growth at G0/G1 phase in BEL-7402 cell line. The complexes can downregulate the expression of Bcl-2 and Bcl-x proteins and upregulate the levels of Bid protein in BEL-7402 cells. The results show that the complexes induce BEL-7402 cell apoptosis through a ROS-mediated mitochondrial dysfunction pathway. In addition, the complexes show strong protein-binding affinities.

Synthesis, characterization, in vitro cytotoxicity and anticancer effects of ruthenium(II) complexes on BEL-7402 cells.

Four new ruthenium(II) polypyridyl complexes [Ru(dmb)2(DQTT)](ClO4)2 (1) (DQTT=12-(1,4-dihydroquinoxalin-6-yl)-4,5,9,14-tetraazabenzo[b]triphenylene, dmb=4,4'-dimethyl-2,2'-bipyridine), [Ru(bpy)2(DQTT)](ClO4)2 (2) (bpy=2,2'-bipyridine), [Ru(phen)2(DQTT)](ClO4)2 (3) (phen=1,10-phenanthroline) and [Ru(dmp)2(DQTT)](ClO4)2 (4) (dmp=2,9-dimethyl-1,10-phenanthroline) were synthesized and characterized by elemental analysis, ESI-MS, (1)H NMR and (13)C NMR. The cytotoxic activity in vitro of the complexes was evaluated against human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines by MTT (3-(4,5-dimethylthiazole)-2,5-diphenyltetrazolium bromide) method. The IC50 values of complexes 1-4 against BEL-7402 cells are 31.8 ± 1.0, 35.8 ± 1.6, 29.0 ± 0.8 and 25.0 ± 0.9 µM, respectively. The morphological apoptosis was investigated with AO/EB (acridine orange/ethidium bromide) and Hoechst 33258 staining methods. The DNA damage was assayed by comet assay. The inhibition of cell migration was evaluated by the wound healing assay. The levels of ROS (reactive oxygen species) and the changes of mitochondrial membrane potential were studied under fluorescent microscope. The percentages in the cells of apoptotic and necrotic cells and the cell cycle arrest were determined by flow cytometry. The expression of Bcl-2 family proteins was investigated by western blot analysis. The results show that the complexes induce BEL-7402 cells apoptosis through a ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulation of the expression of Bcl-2 family proteins.

Cytotoxic activity, DNA damage, cellular uptake, apoptosis and western blot analysis of ruthenium(II) polypyridyl complex against human lung decarcinoma A549 cell.

A new ruthenium(II) polypyridyl complex [Ru(dmp)2(pddppn)](ClO4)2Ru1 was synthesized and characterized. The cytotoxic activity in vitro of the complex was evaluated by MTT method. Ru1 shows high effect on the inhibition of the cell growth against BEL-7402, HeLa, MG-63 and A549 cells with low IC50 values of 1.6±0.4, 9.0±0.8, 1.5±0.2 and 1.5±0.3 µM, respectively. The cellular uptake indicates that Ru1 can enter into the cytoplasm and accumulate in the cell nuclei. Ru1 can induce apoptosis in A549 cells and enhance the levels of reactive oxygen species (ROS) and induce the decrease of mitochondrial membrane potential. In addition, Ru1 can down-regulate the levels of Bcl-2, Bcl-x, Bak, and Bim expression and up-regulate the expression of Bag-1 and Bad. The complex induces apoptosis of A549 cells through an intrinsic ROS-mediated mitochondrial dysfunction pathway, which was accompanied by regulating the expression of caspases and Bcl-2 family proteins.

Effects of daidzein in regards to cytotoxicity in vitro, apoptosis, reactive oxygen species level, cell cycle arrest and the expression of caspase and Bcl-2 family proteins.

In the present study, the in vitro cytotoxicity of daidzein was evaluated in human BEL-7402, A549, HeLa, HepG-2 and MG-63 cancer cell lines. BEL-7402 cells were sensitive to daidzein treatment, with an IC50 value of 59.7±8.1 µM. Daidzein showed no cytotoxic activity toward A549, HeLa, HepG-2 and MG-63 cells. Daidzein increased the levels of reactive oxygen species (ROS) and induced a decrease in mitochondrial membrane potential. Morphological and comet assays showed that daidzein effectively induced apoptosis in BEL-7402 cells. Additionally, daidzein caused cell cycle arrest at the G2/M phase in the BEL-7402 cell line. Daidzein downregulated the expression of Bcl-2, Bcl-x and Baid proteins and upregulated the levels of Bim protein in the BEL-7402 cells. The results demonstrated that daidzein induced BEL-7402 cell apoptosis through an ROS-mediated mitochondrial dysfunction pathway.

Anticancer activity studies of a ruthenium(II) polypyridyl complex against human hepatocellular (BEL-7402) cells.

A Ru(II) polypyridyl complex [Ru(bpy)2(HMSPIP)](ClO4)2 (1) (bpy=2,2'-bipyridine, HMSPIP=2-(4-methylsulfonyl)phenyl-1H-imidazo[4,5-f][1,10] phenanthroline) was synthesized. The IC50 value of the complex against human hepatocellular cell BEL-7402 is 21.6±2.7 µM. The complex shows no cytotoxic activity toward human lung adenocarcinoma cell A549, human osteosarcoma cell MG-63 and human breast cancer cell SK-BR-3 cells. It is easily for complex 1 to be taken up by BEL-7402 cells. The complex can enhance the reactive oxygen species (ROS) levels and induce the decrease in the mitochondrial membrane potential. The complex inhibits the cell growth in BEL-7402 cells at G2/M phase. Complex 1 can regulate the expression of Bcl-2 family proteins. The results show that the complex induces apoptosis of BEL-7402 cells through a ROS-mediated mitochondrial dysfunction pathway.