Synthesis and structure of a new thiazoline-based palladium(II) complex that promotes cytotoxicity and apoptosis of human promyelocytic leukemia HL-60 cells

Cisplatin is one of the most widely used chemotherapeutic agents in the treatment of different tumors but has high toxicity and side effects. Therefore, the synthesis of new chemotherapeutic agents is necessary, so that they are effective in the treatment of cancer while avoiding such toxicity. In this study, we have synthesized and characterized a palladium(II) complex, [PdCl2(µ-PyTT)2]Cl2·4H2O (PdPyTT), with 2-(2-pyridyl)imine-N-(2-thiazolin-2-yl)thiazolidine (PyTT) as a ligand; besides, its cytotoxicity and pro-apoptotic capacity was tested in human promyelocytic leukemia HL-60 cell line. Similar to cisplatin, PdPyTT produced a time- and dose-dependent decrease in cell viability. Additionally, the palladium complex increased both the proportion of cells with apoptotic morphology and the activation of caspase-3 and -9. PdPyTT, like cisplatin, also increased intracellular ROS production and DNA oxidative damage. Therefore, our findings demonstrated the promising application of palladium(II) complexes as novel anti-leukemic agents.

Anticancer Strategy Targeting Cell Death Regulators: Switching the Mechanism of Anticancer Floxuridine-Induced Cell Death from Necrosis to Apoptosis

Cell death can be broadly characterized as either necrosis or apoptosis, depending on the morphological and biochemical features of the cell itself. We have previously reported that the treatment of mouse mammary carcinoma FM3A cells with the anticancer drug floxuridine (FUdR) induces necrosis in the original clone F28-7 but apoptosis in the variant F28-7-A. We have identified regulators, including heat shock protein 90, lamin-B1, cytokeratin-19, and activating transcription factor 3, of cell death mechanisms by using comprehensive gene and protein expression analyses and a phenotype-screening approach. We also observed that the individual inhibition or knockdown of the identified regulators in F28-7 results in a shift from necrotic to apoptotic morphology. Furthermore, we investigated microRNA (miRNA, miR) expression profiles in sister cell strains F28-7 and F28-7-A using miRNA microarray analyses. We found that several unique miRNAs, miR-351-5p and miR-743a-3p, were expressed at higher levels in F28-7-A than in F28-7. Higher expression of these miRNAs in F28-7 induced by transfecting miR mimics resulted in a switch in the mode of cell death from necrosis to apoptosis. Our findings suggest that the identified cell death regulators may play key roles in the decision of cell death mechanism: necrosis or apoptosis.

Indocyanine Green Loaded Modified Mesoporous Silica Nanoparticles as an Effective Photothermal Nanoplatform

Photothermal therapy possesses great advantages for the treatment of drug-resistant tumors. Herein, Near Infrared (NIR)-triggered photothermal nanoparticles were developed through loading indocyanine green (ICG), a kind of NIR dye, into amino group-modified silica nanoparticles (SiO2-NH2 NPs). SiO2-NH2 NPs were prepared with immobilization of the amino groups into the framework of silica nanoparticles (SiO2 NPs) by employing (3-aminopropyl)-triethoxysilane (APTES). Before and after the modification of the amino group, the particle sizes of SiO2 NPs showed similar value, around 100 nm. ICG was further adsorbed into SiO2-NH2 NPs by electrostatic attraction to enable SiO2-NH2@ICG NPs as a kind of photothermal agent. The loading rate of ICG to SiO2-NH2 was greatly increased compared to unmodified SiO2, and the stability of ICG was also improved. Moreover, the SiO2-NH2@ICG NPs exhibited efficient photothermal effects due to ICG transforming laser power into local heat through the connected ICG, when NIR laser irradiation turned on for a couple of minutes. Finally, the in vitro antitumor efficacy of SiO2-NH2@ICG NPs was investigated by recording cell proliferation rate and further chronicled the apoptotic morphology evidence by a Calcein-AM/PI fluorescent staining assay, indicating the efficient photothermal targeted therapy for the HepG2 tumor cells.

Effects of macrophage depletion on characteristics of cervix remodeling and pregnancy in CD11b-dtr mice

To test the hypothesis that macrophages are essential for remodeling the cervix in preparation for birth, pregnant homozygous CD11b-dtr mice were injected with diphtheria toxin (DT) on days 14 and 16 postbreeding. On day 15 postbreeding, macrophages (F4/80+) were depleted in cervix and kidney, but not in liver, ovary, or other non-reproductive tissues in DT—compared to saline—treated dtr mice or wild-type controls given DT or saline. Within 24 h of DT-treatment, the density of cell nuclei and macrophages declined in cervix stroma in dtr mice versus controls, but birefringence of collagen, as an indication of extracellular cross-linked structure, remained unchanged. Only in the cervix of DT-treated dtr mice was an apoptotic morphology evident in macrophages. DT-treatment did not alter the sparse presence or morphology of neutrophils. By day 18 postbreeding, macrophages repopulated the cervix in DT-treated dtr mice so that the numbers were comparable to that in controls. However, at term, evidence of fetal mortality without cervix ripening occurred in most dtr mice given DT—a possible consequence of treatment effects on placental function. These findings suggest that CD11b+ F4/80+ macrophages are important to sustain pregnancy and are required for processes that remodel the cervix in preparation for parturition.

Antitumor Effect of n-Butylidenephthalide Encapsulated on B16/F10 Melanoma Cells In Vitro with a Polycationic Liposome Containing PEI and Polyethylene Glycol Complex

Advanced melanoma can metastasize to distal organs from the skin and yield an aggressive disease and poor prognosis even after treatment with chemotherapeutic agents. The compound n-Butylidenephthalide (BP) is isolated from Angelica sinensis, which is used to treat anemia and gynecological dysfunction in traditional Chinese medicine. Studies have indicated that BP can inhibit cancers, including brain, lung, prostate, liver, and colon cancers. However, because BP is a natural hydrophobic compound, it is quickly metabolized by the liver within 24 h, and thus has limited potential for development in cancer therapy. This study investigated the anticancer mechanisms of BP through encapsulation with a novel polycationic liposome containing polyethylenimine (PEI) and polyethylene glycol complex (LPPC) in melanoma cells. The results demonstrated that BP/LPPC had higher cytotoxicity than BP alone and induced cell cycle arrest at the G0/G1 phase in B16/F10 melanoma cells. The BP/LPPC-treated cell indicated an increase in subG1 percentage and TUNEL positive apoptotic morphology through induction of extrinsic and intrinsic apoptosis pathways. The combination of BP and LPPC and clinical drug 5-Fluorouracil had a greater synergistic inhibition effect than did a single drug. Moreover, LPPC encapsulation improved the uptake of BP values through enhancement of cell endocytosis and maintained BP cytotoxicity activity within 24 h. In conclusion, BP/LPPC can inhibit growth of melanoma cells and induce cell arrest and apoptosis, indicating that BP/LPPC has great potential for development of melanoma therapy agents.

Antitumor and Immunomodulatory Effect of Gastrodia elata on Colon Cancer In Vitro and In Vivo

Gastrodia elata Blume (GE) is a well-known kind of herb that has been used in traditional medicine for thousands of years. The extrusion of raw materials from it could improve flavor and enhance bioavailability in food and drug development. The purpose of this study is to investigate antitumor and immune boosting effects of extruded GE in human colon carcinoma cells, splenocytes, and mice-bearing CT26 colon carcinoma cell. Treatment with 100[Formula: see text][Formula: see text]g/mL of extruded GE decreased cell viability and induced the expression of Caspase-3 and Bax in HT29 cells ([Formula: see text]). When we performed DAPI staining, apoptotic bodies with condensed chromatin and fragmented nuclei, known as indicative of apoptotic morphology, increased 24[Formula: see text]h after treatment with 100[Formula: see text][Formula: see text]g/mL of extruded GE. Treatments with extruded GE significantly promoted splenocyte proliferation and IL-2 or IFN-[Formula: see text] secretion, compared with that of control cells ([Formula: see text]). The administration of extruded GE of 200 mg/kg/day decreased tumor growth and Ki-67 or [Formula: see text]-catenin expression in mice ([Formula: see text]). Additionally, we investigated the contents of compounds in extruded GE extracts using ultra performance liquid chromatography. The contents of p-hydroxylbenzyl alcohol and p-hydroxybenzaldehyde in extruded GE were 2.97[Formula: see text]mg/g and 0.04[Formula: see text]mg/g, respectively. It was supposed that antitumor and immunomodulatory effects of extruded GE might exert by the p-hydroxylbenzyl alcohol and p-hydroxybenzaldehyde of many compositions analyzed from extruded GE. These results suggest that extruded GE have the potential to be developed into a natural pharmaceutical and functional food as a cancer chemopreventive agent.

Effect of puerarin on human choriocarcinoma cells

Objective: To discuss the effect of puerarin on human choriocarcinoma cells. Methods: Survival rates under puerarin monotherapy, fluorouracil (5-FU) monotherapy and puerarin in combination with 5-FU were detected by MTT assay. Apoptotic morphology was observed with Hoechst 33258 staining. Apoptosis rates were detected with flow cytometry. Expressions of AKT, mechanistic target of rapamycin (mTOR), and P70S6K mRNAs and phosphorylated proteins were detected by RT-PCR and Western blot. Tumor-bearing mice were administered puerarin and puerarin+5-FU, and serum levels of β-human chorionic gonadotropin (β-HCG) were measured. Results: Proliferation inhibition and apoptosis rates of JEG-3 cells were positively correlated with puerarin concentration, which increased in the puerarin+5-FU group. Expression levels of AKT, mTOR, P70S6K mRNAs, and phosphorylated proteins decreased significantly after action of puerarin at different concentrations. With increasing puerarin concentration, expression of cleaved-caspase-3 in JEG-3 cells increased, whereas that of Bcl-2 decreased. Puerarin significantly inhibited tumor growth in choriocarcinoma-bearing SCID mice. Serum β-HCG levels were significantly lower than those of control group after administration. Magnitude of β-HCG decline was positively correlated with concentration. Conclusion: Puerarin+5-FU inhibited proliferation of JEG-3 choriocarcinoma cells and promoted their apoptosis, being associated with the mTOR signaling pathway.

The Effect of T-7 Peptide on Human Non-Small-Cell Carcinoma A549 Cells

7 peptide of Tumstatin(T-7 peptide) is composed of 185-191 amino acids. To study T-7 peptide antitumor activity to human non-small-cell carcinoma(A549), T-7 peptide was designed and synthesized by amino acid synthesizer. Its purity ran up to 98.45% by HPLC and MS. The effect of T-7 peptide on A549 cell growth was observed by MTT assay, growth curve and transmission electron microscopy(TEM). T-7 peptide had the effects of suppressing A549 cell growth and promoting its apoptosis, showing dose- and time-dependent. Its IC50 was 92.84 μg/ml. TEM also revealed that A549 cell treated with T-7 peptide appeared apoptotic morphology,such as cell pyknosis and mitochondrial vacuoles formed. While T-7 peptide had little effect on human umbilical vein endothelial cells(ECV304). These researches were significant to treat human non-small-cell carcinoma in the future.

Apoptosis Induction in Primary Human Colorectal Cancer Cell Lines and Retarded Tumor Growth in SCID Mice by Sulforaphane

We have investigated the anticancer effects of the dietary isothiocyanate sulforaphane (SFN) on colorectal cancer (CRC), using primary cancer cells lines isolated from five Taiwanese colorectal cancer patients as the model for colorectal cancer. SFN-treated cells accumulated in metaphase (SFN 6.25 μM) and subG1 (SFN 12.5 and 25 μM) as determined by flow cytometry. In addition, treated cells showed nuclear apoptotic morphology that coincided with an activation of caspase-3, and loss of mitochondrial membrane potential(ΔΨm). Incubations at higher SFN doses (12.5 and 25 μM) resulted in cleavage of procaspase-3 and elevated caspase-2, -3, -8, and -9 activity, suggesting that the induction of apoptosis and the sulforaphane-induced mitosis delay at the lower dose are independently regulated. Daily SFN s.c. injections (400 micromol/kg/d for 3 weeks) in severe combined immunodeficient mice with primary human CRC (CP1 to CP5) s.c. tumors resulted in a decrease of mean tumor weight by 70% compared with vehicle-treated controls. Our findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may have antitumor activity in established colorectal cancer.

The role of N-acetyl-cysteine in the lung remote injury after hepatic ischemia and reperfusion in rabbits

PURPOSE: To study the lesions in the lung of rabbits caused by ischemia/reperfusion hepatic (I/R) after the use of N-acetyl-cysteine (NAC). METHODS: Twenty-four rabbits distributed in two groups: control group GI (n = 12) 5% glucose solution and experiment group GII (n = 12) NAC. The animals were pre-anesthetized with 1% acepromazine maleate and anesthetized with ketamine 10% and 2% xylazine intramuscularly. The GI and GII were given glucose solution intravenously or NAC 15min before occlusion of the hepatic pedicle (30 min). After the period of reperfusion of 24h (n = 6) or 48h (n = 6), liver and lung samples were collected for histology and immunohistochemistry to assess the impairment of cell. RESULTS: The animals of GII and GII-24h-48h showed parenchyma liver close to normal, when using NAC. The GII and GII-24h-48h showed lower thickness of alveolar cells that GI and GI-24h-48h. The expression of caspase 3 in lung cells GII presented smaller value compared to the GI group. CONCLUSION: N-acetyl-cysteine administered 15min prior to the injury ischemia/reperfusion had a significant protective role by minimizing lung injury and apoptotic morphology in the period observed.