HDAC/NAMPT dual inhibitors overcome initial drug-resistance in p53-null leukemia cells.

The occurrence of cancer is closely related to metabolism and epigenetics. Histone deacetylases (HDACs) play a crucial role in the regulation of gene expression as epigenetic regulators, while nicotinamide phosphoribosyltransferase (NAMPT) is significantly involved in maintaining cellular metabolism. In this study, we rationally designed a series of novel HDAC/NAMPT dual inhibitors based on the structural similarity between HDAC and NAMPT inhibitors. The representative compounds 39a and 39h exhibit significant selective inhibitory activity on HDAC1-3 with IC50 values of 0.71-25.1 nM, while displaying modest activity against NAMPT. Compound 39h did not exhibit inhibitory activity against 370 kinases, demonstrating its target specificity. These two compounds exhibit potent anti-proliferative activity in multiple leukemia cell lines with low nanomolar IC50s. It is worth noticing that the dual inhibitors 39a and 39h overcome the primary resistance of HDAC or NAMPT single target inhibitor in p53-null AML cell lines, with the induction of apoptosis-related cell death. NMN recovers the cell death induced by HDAC/NAMPT dual inhibitors, which indicates the lethal effects are caused by the inhibition of NAD biosynthesis pathway as well as HDAC. This research provides an effective strategy to overcome the limitations of HDAC inhibitors in treating p53-null leukemia.

Recent advance in phytonanomedicine and mineral nanomedicine delivery system of the treatment for acute myeloid leukemia.

Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy caused by excessive proliferation of myeloblasts. Classical chemotherapies and cell transplantation therapies have remarkable efficacy in AML treatment; however, 30-40% of patients relapsed or had refractory disease. The resistance of AML is closely related to its inherent cytogenetics or various gene mutations. Recently, phytonanomedicine are found to be effective against resistant AML cells and have become a research focus for nanotechnology development to improve their properties, such as increasing solubility, improving absorption, enhancing bioavailability, and maintaining sustained release and targeting. These novel phytonanomedicine and mineral nanomedicine, including nanocrystals, nanoemulsion, nanoparticles, nanoliposome, and nanomicelles, offer many advantages, such as flexible dosages or forms, multiple routes of administration, and curative effects. Therefore, we reviewed the application and progress of phytomedicine in AML treatment and discussed the limitations and future prospects. This review may provide a solid reference to guide future research on AML treatment.

Downreguation of FoxM1 by miR-214 inhibits proliferation and migration in hepatocellular carcinoma.

The FoxM1 transcription factor plays an important role in the progression of HCC. Therefore, it is necessary to study cell regulation of FoxM1. In this study, we determined the expression of miR-214 and it was inversely associated with FoxM1 protein level in HCC; and suppression of FoxM1 translation by miR-214 mimics. We found that miR-214 targeted the 3'untranslated region of FoxM1 mRNA. In addition, the study found that DLX1 was the direct target of FoxM1 in HCC. Downregulation of FoxM1 inhibits the proliferation, migration, and invasion of HCC cells by miR-214. These results indicate that miR-214 may be used as a completely new molecular target by influencing FoxM1 expression in HCC.

MicroRNA-18a promotes proliferation and metastasis in hepatocellular carcinoma via targeting KLF4.

MicroRNAs (miRNAs) are short, non-coding and endogenous RNAs that played as important roles in the proliferation and metastasis of tumors. In this study, we determined the role of miR-18a in the regulation of HCC cell motility. We showed that miR-18a expression was upregulated in human HCC tissues and cell lines. Moreover, Elevated expression of miR-18a promoted the HCC cell proliferation and migration. KLF4 was identified as a direct target of miR-18a in HCC cells. Furthermore, overexpression of KLF4 attenuated the effects of miR-18a on the regulation of HCC cell motility. The expression of KLF4 was negatively associated with the expression of miR-18a expression in HCC tissues. We also showed that the cell cycle inhibitor p21 was aberrantly downregulated in HCC cells, whereas this inhibition was reversed by miR-18a inhibitor. These data indicated that miR-18a may play a positive role in hepatocellular carcinoma by promoting the proliferation and migration of HCC cells through targeting KLF4 as well as downstream p21.

Nedaplatin or oxaliplatin combined with paclitaxel and docetaxel as first-line treatment for patients with advanced non-small cell lung cancer.

BACKGROUND: Both nedaplatin and oxaliplatin combined with paclitaxel or docetaxel have demonstrated potent activity in advanced non-small cell lung cancer (NSCLC) patients, but there is no study comparing the difference between these 2 chemotherapy regimens. The aim of this study was to evaluate and compare the efficacy and safety between the combination chemotherapy of nedaplatin or oxaliplatin plus paclitaxel and docetaxel in patients with advanced NSCLC. MATERIAL AND METHODS: We retrospectively reviewed patients with stage III-IV unresectable NSCLC from 1 January 2010 to 31 December 2013 at Southwest Hospital. They all received nedaplatin (80 mg/m2, nedaplatin group) or oxaliplatin (130 mg/m2, oxaliplatin group) combined with paclitaxel (175 mg/m2) or docetaxel (75 mg/m2) as first-line treatment. RESULTS: There are 174 patients enrolled - 123 patients in the nedaplatin group and 51 patients in the oxaliplatin group. The objective response rates were 47.3% and 34.1% and the disease control rates were 87.5% and 79.5% in nedaplatin and oxaliplatin groups, respectively. The progression-free survival time was 10.4 months and 9.6 months (p=0.722) and the overall survival time was 18.5 months and 25.5 months in the nedaplatin and oxaliplatin groups, respectively (p=0.09). Total toxicity was greater in the oxaliplatin group (p=0.008), but there is no significant difference among ¾ grade adverse events between the 2 groups (P=0.595). CONCLUSIONS: The effect of nedaplatin plus paclitaxel and docetaxel is the same as oxaliplatin plus paclitaxel and docetaxel, and the toxicity of nedaplatin is well tolerate as first-line treatment for patients with advanced NSCLC.

A game-theoretical approach to multimedia social networks security.

The contents access and sharing in multimedia social networks (MSNs) mainly rely on access control models and mechanisms. Simple adoptions of security policies in the traditional access control model cannot effectively establish a trust relationship among parties. This paper proposed a novel two-party trust architecture (TPTA) to apply in a generic MSN scenario. According to the architecture, security policies are adopted through game-theoretic analyses and decisions. Based on formalized utilities of security policies and security rules, the choice of security policies in content access is described as a game between the content provider and the content requester. By the game method for the combination of security policies utility and its influences on each party's benefits, the Nash equilibrium is achieved, that is, an optimal and stable combination of security policies, to establish and enhance trust among stakeholders.