Effectiveness of the Histone Deacetylase Inhibitor (S)-2 Against LNCaP and PC3 Human Prostate Cancer Cells.

Effectiveness of the Histone Deacetylase Inhibitor (S)-2 against LNCaP and PC3 Human Prostate Cancer Cells.

PLoS One. 2013; 8(3): e58267
Laurenzana A, Balliu M, Cellai C, Romanelli MN, Paoletti F

Histone deacetylase inhibitors (HDACi) represent a promising class of epigenetic agents with anticancer properties. Here, we report that (S)-2, a novel hydroxamate-based HDACi, shown previously to be effective against acute myeloid leukemia cells, was also a potent inducer of apoptosis/differentiation in human prostate LNCaP and PC3 cancer cells. In LNCaP cells (S)-2 was capable of triggering H3/H4 histone acetylation, H2AX phosphorylation as a marker of DNA damage and producing G/G cell cycle arrest. Consistently, (S)-2 led to enhanced expression of both the protein and mRNA p21 levels in LNCaP cells but, contrary to SAHA, not in normal non-tumorigenic prostate PNT1A cells. Mechanistic studies demonstrated that (S)-2-induced apoptosis in LNCaP cells developed through the cleavage of pro-caspase 9 and 3 and of poly(ADP-ribose)-polymerase accompanied by the dose-dependent loss of mitochondrial membrane potential. Indeed, the addition of the pan-caspase inhibitor Z-VAD-fmk greatly reduced drug-mediated apoptosis while the antioxidant -acetyl-cysteine was virtually ineffective. Importantly, preliminary data with nude mice xenografted with LNCaP cells showed that (S)-2 prompted a decrease in the tumor volume and an increase in H2AX phosphorylation within the cancer cells. Moreover, the highly metastatic prostate cancer PC3 cells were also sensitive to (S)-2 that: i) induced growth arrest and moderate apoptosis; ii) steered cells towards differentiation and neutral lipid accumulation; iii) reduced cell invasiveness potential by decreasing the amount of MMP-9 activity and up-regulating TIMP-1 expression; and iv) inhibited cell motility and migration through the Matrigel. Overall, (S)-2 has proven to be a powerful HDACi capable of inducing growth arrest, cell death and/or differentiation of LNCaP and PC3 prostate cancer cells and, due to its low toxicity and efficacy , might also be of clinical interest to support conventional prostate cancer therapy. HubMed – drug


Ultrasound exposure improves the targeted therapy effects of galactosylated docetaxel nanoparticles on hepatocellular carcinoma xenografts.

PLoS One. 2013; 8(3): e58133
Wei H, Huang J, Yang J, Zhang X, Lin L, Xue E, Chen Z

The distribution of targeted nanoparticles in tumor tissue is affected by a combination of various factors such as the physicochemical properties of the nanoparticles, tumor hemoperfusion and tumor vascular permeability. In this study, the impact of the biological effects of ultrasound on nanoparticle targeting to liver carcinoma was explored.The copolymer MePEG-PLGA was used to prepare the galactosylated docetaxel nanoparticles (GDN), and the physical and chemical properties as well as the acute toxicity were then assayed. The impact of ultrasound exposure (UE) on tumor hemoperfusion was observed by contrast-enhanced ultrasonography (CEUS), and the distribution of docetaxel in tumors and liver were detected by high performance liquid chromatography (HPLC). In the GDN combined with UE treatment group, the mice were injected intravenously with GDN, followed by ultrasound exposure on the human hepatocellular carcinoma xenografts. Twenty-eight days post-administration, the tumor growth inhibition rate was calculated, and the expression of Survivin and Ki67 in tumor tissues were determined by immunohistochemistry assay and quantitative real-time PCR.The mean size of prepared liver-targeting nanoparticles GDN was 209.3 nm, and the encapsulation efficiency was 72.28%. The median lethal dose of GDN was detected as 219.5 mg/kg which was about four times higher than that of docetaxel. After ultrasound exposure, the tumor peak – base intensity difference value, examined by CEUS, increased significantly. The drug content in the tumor was 1.96 times higher than in the GDN treated control. , GDN intravenous injection combined with ultrasound exposure therapy achieved the best anti-tumor effect with a tumor growth inhibition rate of 74.2%, and the expression of Survivin and Ki67 were significantly decreased as well.Ultrasound exposure can improve targeting nanoparticles accumulation in the tumor, and achieve a synergism antitumor effect on the hepatocellular carcinoma xenografts. HubMed – drug


Transmission Patterns of HIV-Subtypes A/AE versus B: Inferring Risk-Behavior Trends and Treatment-Efficacy Limitations from Viral Genotypic Data Obtained Prior to and during Antiretroviral Therapy.

PLoS One. 2013; 8(3): e57789
Avidor B, Turner D, Mor Z, Chalom S, Riesenberg K, Shahar E, Pollack S, Elbirt D, Sthoeger Z, Maayan S, Olshtain-Pops K, Averbuch D, Chowers M, Istomin V, Anis E, Mendelson E, Ram D, Levy I, Grossman Z

HIV subtypes A and CRF01_AE (A/AE) became prevalent in Israel, first through immigration of infected people, mostly intravenous-drug users (IVDU), from Former Soviet-Union (FSU) countries and then also by local spreading. We retrospectively studied virus-transmission patterns of these subtypes in comparison to the longer-established subtype B, evaluating in particular risk-group related differences. We also examined to what extent distinct drug-resistance patterns in subtypes A/AE B reflected differences in patient behavior and drug-treatment history.Reverse-transcriptase (RT) and protease sequences were retrospectively analyzed along with clinical and epidemiological data. MEGA, ClusalX, and Beast programs were used in a phylogenetic analysis to identify transmission networks.318 drug-naive individuals with A/AE or patients failing combination antiretroviral therapy (cART) were identified. 61% were IVDU. Compared to infected homosexuals, IVDU transmitted HIV infrequently and, typically, only to a single partner. 6.8% of drug-naive patients had drug resistance. Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations. Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype.While sizable transmission networks occur in infected homosexuals, continued HIV transmission among IVDU in Israel is largely sporadic and the rate is relatively modest, as is that of drug-resistance transmission. Deviation of drug-naive A/AE sequences from subtype-B consensus sequence, documented here, may subtly affect drug-resistance pathways. Conspicuous differences in overall drug-resistance that are manifest before regimen stratification can be largely explained in terms of treatment history, by the different efficacy/adherence limitations of older newer regimens. The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation. HubMed – drug