Modified nodal stage of esophageal cancer based on the evaluation of the hazard rate of the negative and positive lymph node.

BACKGROUND: The study aimed to propose a modified N stage of esophageal cancer (EC) on the basis of the number of positive lymph node (PLN) and the number of negative lymph node (NLN) simultaneously. METHOD: Data from 13,491 patients with EC registered in the SEER database were reviewed. The parameters related to prognosis were investigated using a Cox proportional hazards regression model. A modified N stage was proposed based on the cut-off number of the re-adjusted ratio of the number of PLN (numberPLN) to the number of NLN (numberNLN), which were derived from the comparison of the hazard rate (HR) of numberPLN and numberNLN. The modified N stage was confirmed using the cross-validation method with the training and validation cohort, and it was also compared to the N stage from the American Joint Committee on Cancer (AJCC) staging system (7th edition) using Receiver Operating Characteristic (ROC) curve analysis. RESULTS: The numberPLN on prognosis was 1.042, while numberNLN was 0.968. The modified N stage was defined as follows: N1 stage: the ratio range was from 0 to 0.21; N2 stage: more than 0.21, but no more than 0.48; N3 stage: more than 0.48. The log-rank test indicated that significant survival differences were confirmed among the N1, N2 and N3 sub-groups of patients in the training population. The difference of all the patients using the modified N stage method were more significant than AJCC N stage. The result of ROC analysis indicated that the modified N stage could represent the N stage of EC more accurately. CONCLUSION: The modified N stage based on the re-adjusted ratio of numberPLN to numberNLN can evaluate tumor stage more accurately than the traditional N stage.

LncRNA PSMA3-AS1 Promotes Lung Cancer Growth and Invasion via Sponging MiR-4504.

BACKGROUND: Long noncoding RNAs (lncRNAs) have close correlation with tumorigenesis. And how lncRNAs participate in lung cancer require investigation in-depth. The aim of this study was to determine the role of lncRNA PSMA3-AS1 in lung cancer progression. METHODS: PSMA3-AS1 expression was analyzed via qRT-PCR. Kaplan-Meier method was used to analyze survival rate based on PSMA3-AS1 value. Proliferation was measured via CCK8 and colony formation assays. Transwell assay was utilized to examine migration and invasion. Luciferase reporter assay and RNA pulldown assay were utilized to analyze the interaction between PSMA3-AS1 and miR-4504. RESULTS: PSMA3-AS1 expression was upregulated in lung cancer tissues and cell lines. PSMA3-AS1 expression was positively correlated with clinical stage and metastasis. PSMA3-AS1 overexpression predicted a poor prognosis in lung cancer patients. PSMA3-AS1 knockdown suppressed proliferation, migration and invasion of lung cancer cells. Through bioinformatics analysis, PSMA3-AS1 was predicted to sponge miR-4504. MiR-4504 expression was inhibited by PSMA3-AS1. And inhibition of miR-4504 reversed the effects of PSMA3-AS1 depletion. CONCLUSION: PSMA3-AS1 promotes the tumorigenesis of lung cancer through inhibiting miR-4504.

Co-delivery of vincristine and quercetin by nanocarriers for lymphoma combination chemotherapy.

PURPOSE: Chemotherapy is the current standard treatment for Non-Hodgkin's lymphoma (NHL). Combination therapy is emerging as an important strategy for a better long-term prognosis with decreased side effects, maximized therapeutic effect. The aim of this study is to deliver vincristine (VCR) and quercetin (QU) with synergistic drug ratios through lipid-polymeric nanocarriers (LPNs) for the lymphoma combination chemotherapy METHODS: In this present study, we constructed VCR and QU dual-loaded LPNs (VCR/QU LPNs) and investigated their antitumor efficacy in vitro cell culture models and a tumor xenograft mouse model. RESULTS: The formulated VCR/QU LPNs exhibited nano-size, negative zeta potential with sustained release profile in vitro. The dual drug loaded LPNs exhibited the best antitumor efficacy in vitro and in vivo. CONCLUSION: It could be concluded that VCR/QU LPNs can combine the efficiency of these two drugs, bring about synergistic effect. Co-encapsulation of VCR and QN in the same LPNs has potential as a novel therapeutic approach to overcome chemo-resistant lymphoma.

Ruthenium complexes with phenylterpyridine derivatives target cell membrane and trigger death receptors-mediated apoptosis in cancer cells.

Elucidation of the communication between metal complexes and cell membrane may provide useful information for rational design of metal-based anticancer drugs. Herein we synthesized a novel class of ruthenium (Ru) complexes containing phtpy derivatives (phtpy = phenylterpyridine), analyzed their structure-activity relationship and revealed their action mechanisms. The result showed that, the increase in the planarity of hydrophobic Ru complexes significantly enhanced their lipophilicity and cellular uptake. Meanwhile, the introduction of nitro group effectively improved their anticancer efficacy. Further mechanism studies revealed that, complex (2c), firstly accumulated on cell membrane and interacted with death receptors to activate extrinsic apoptosis signaling pathway. The complex was then transported into cell cytoplasm through transferrin receptor-mediated endocytosis. Most of the intracellular 2c accumulated in cell plasma, decreasing the level of cellular ROS, inducing the activation of caspase-9 and thus intensifying the apoptosis. At the same time, the residual 2c can translocate into cell nucleus to interact with DNA, induce DNA damage, activate p53 pathway and enhance apoptosis. Comparing with cisplatin, 2c possesses prolonged circulation time in blood, comparable antitumor ability and importantly, much lower toxicity in vivo. Taken together, this study uncovers the role of membrane receptors in the anticancer actions of Ru complexes, and provides fundamental information for rational design of membrane receptor targeting anticancer drugs.

Novel transferrin modified and doxorubicin loaded Pluronic 85/lipid-polymeric nanoparticles for the treatment of leukemia: In vitro and in vivo therapeutic effect evaluation.

PURPOSE: Childhood leukemia is a common malignant disease in children. Doxorubicin (DOX) was widely used for the treatment of leukemia. However, severe toxic side effects and drug resistance are the major limitations of DOX. Nanocarriers offer the opportunity to overcome these drawbacks, there are many attempts to enhance the activity of DOX against drug resistance. This study aimed to develop a novel transferrin (Tf) modified and doxorubicin (DOX) loaded Pluronic 85/lipid-polymeric nanoparticles for the treatment of leukemia. METHODS: In this study, a novel targeted ligand: transferrin-polyethylene glycol-oleic acid (Tf-PEG-OA) was synthesized. Tf modified and DOX loaded Pluronic 85/lipid-polymeric nanoparticles (Tf-DOX P85/LPNs) were prepared via the self-assembly of PLGA, P85, stearic acid and Tf-PEG-OA using the nanoprecipitation method. The physicochemical properties of LPNs were characterized. In vitro and in vivo anti-tumor efficacy of LPNs was evaluated in human promyelocytic leukemia cell line (HL-60 cells) and DOX resistance HL-60 cell line (HL-60/DOX cells) including the relevant animal models. RESULTS: Tf-DOX P85/LPNs displayed strong anti-tumor ability on both HL-60 cells and HL-60/DOX cells than other formulations used as contrast. Also, in HL-60/DOX bearing animal models, Tf-DOX P85/LPNs exhibited the highest efficiency as well as the lowest systemic toxicity. CONCLUSION: The results indicated that Tf P85/LPNs is a promising platform to enhance efficacy, reduce toxicity and overcome drug resistance of DOX for the treatment of leukemia.

Rational Design of Ruthenium Complexes Containing 2,6-Bis(benzimidazolyl)pyridine Derivatives with Radiosensitization Activity by Enhancing p53 Activation.

The rational design of metal-based complexes is an effective strategy for the discovery of potent sensitizers for use in cancer radiotherapy. In this study, we synthesized three ruthenium complexes containing bis-benzimidazole derivatives: Ru(bbp)Cl3 (1), [Ru(bbp)2 ]Cl2 (2 a) (in which bbp=2,6-bis(benzimidazol-1-yl)pyridine), and [Ru(bbp)2]Cl2 (2 b) (where bbp=2,6-bis-(6-nitrobenzimidazol-2-yl)pyridine). We evaluated their radiosensitization capacities in vitro and mechanisms of action. Complex 2 b was found to be particularly effective in sensitizing human melanoma A375 cells toward radiation, with a sensitivity enhancement ratio of 2.4. Along with this potency, complex 2 b exhibited a high degree of selectivity between human cancer and normal cells. Mechanistic studies revealed that 2 b promotes radiation-induced accumulation of intracellular reactive oxygen species (ROS) by reacting with cellular glutathione (GSH) and then causing DNA stand breaks. The subsequent DNA damage induces phosphorylation of p53 (p-p53) and upregulates the expression levels of p21, which inhibits the expression of cyclin-B, leading to G2M arrest. Moreover, p-p53 activates caspases-3 and -8, triggers cleavage of poly(ADP-ribose) polymerase (PARP), finally resulting in apoptosis. Taken together, the results of this study provide a strategy for the design of ruthenium-based radiosensitizers for use in cancer therapy.

A selenium-containing ruthenium complex as a cancer radiosensitizer, rational design and the important role of ROS-mediated signalling.

A novel selenium-containing ruthenium complex Ru(phtpy)(phenSe)Cl(ClO4) (phtpy = 4-phenyl-2,2':6',2''-terpyridine, phenSe = 2-selenicimidazole[4,5-f]1,10-phenanthroline) has been synthesized and found be able to enhance radiation-induced DNA damage through superoxide overproduction, which leads to G2/M arrest and apoptosis in cancer cells by activating ROS-mediated pathways.

Ruthenium polypyridyl complexes as inducer of ROS-mediated apoptosis in cancer cells by targeting thioredoxin reductase.

TrxR is an NADPH-dependent selenoenzyme upregulated in a number of cancers. It plays a pivotal role in cancer progression and represents an increasingly attractive target for anticancer drugs. The limitations of cisplatin in cancer treatment have motivated the extensive investigation to other metal complexes, especially ruthenium (Ru) complexes. In this study, we present the in vitro biological evaluation of four Ru(II) polypridyl complexes with diimine ligands, namely, [Ru(bpy)3](2+) (1), [Ru(phen)3](2+) (2), [Ru(ip)3](2+) (3), [Ru(pip)3](2+) (4) (bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, ip = imidazole[4,5-f][1,10]phenanthroline, pip = 2-phenylimidazo[4,5-f][1,10]phenanthroline), and demonstrate that they exhibit antiproliferative activities against A375 human melanoma cells through inhibition of TrxR. As the planarity of the structure increases, their TrxR-inhibitory effects and in vitro anticancer activities were enhanced. Among them, complex 4 exhibited higher antiproliferative activity than cisplatin, and the TrxR-inhibitory potency of 4 was more effective than auranofin, a positive TrxR inhibitor. Complex 4 suppressed the cancer cell growth through induction of apoptosis as evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Moreover, complex 4 was able to localize in mitochondria and therein induced ROS-dependent apoptosis by inhibition of TrxR activity. Activation of MAPKs, AKT, DNA damage-mediated p53 phosphorylation and inhibition of VEGFR signaling were also triggered in cells exposed to complex 4. On the basis of this evidence, we suggest that Ru polypyridyl complexes could be developed as TrxR-targeted agents that demonstrate application potentials for treatment of cancers.

Zinc(II) complexes containing bis-benzimidazole derivatives as a new class of apoptosis inducers that trigger DNA damage-mediated p53 phosphorylation in cancer cells.

In the present study, two zinc(II) complexes containing bis-benzimidazole derivatives, Zn(bpbp)Cl2 (1) and [Zn(bpbp)2](ClO4)2·CH3CH2OH·H2O (2) (bpbp = 2,6-bis(1-phenyl-1H-benzo[d]imidazol-2-yl)pyridine), have been designed, synthesized and evaluated for their in vitro anticancer activities. The underlying molecular mechanisms through which they caused the cancer cell death were also elucidated. The complexes were identified as potent antiproliferative agents against a panel of five human cancer cell lines by comparing with cisplatin. Complex 2 demonstrated dose-dependent growth inhibition on MCF-7 human breast carcinoma cells with IC50 at 2.9 µM. Despite this potency, the complexes possessed great selectivity between human cancer cells and normal cells. Induction of apoptosis in MCF-7 cells by complex 2 was evidenced by accumulation of sub-G1 cell population, DNA fragmentation and nuclear condensation. Further investigation on intracellular mechanisms revealed that complex 2 was able to induce p53-dependent apoptosis in cancer cells by triggering DNA damage. On the basis of this evidence, we suggest that Zn(II) complexes containing bis-benzimidazole derivatives may be candidates for further evaluation as chemotherapeutic agents for human cancers.