PTEN deletion in luminal cells of mature prostate induces replication stress and senescence in vivo.

Genetic ablation of the tumor suppressor PTEN in prostatic epithelial cells (PECs) induces cell senescence. However, unlike oncogene-induced senescence, no hyperproliferation phase and no signs of DNA damage response (DDR) were observed in PTEN-deficient PECs; PTEN loss-induced senescence (PICS) was reported to be a novel type of cellular senescence. Our study reveals that PTEN ablation in prostatic luminal epithelial cells of adult mice stimulates PEC proliferation, followed by a progressive growth arrest with characteristics of cell senescence. Importantly, we also show that proliferating PTEN-deficient PECs undergo replication stress and mount a DDR leading to p53 stabilization, which is however delayed by Mdm2-mediated p53 down-regulation. Thus, even though PTEN-deficiency induces cellular senescence that restrains tumor progression, as it involves replication stress, strategies promoting PTEN loss-induced senescence are at risk for cancer prevention and therapy.

The application of Fe3O4 nanoparticles in cancer research: a new strategy to inhibit drug resistance.

Although much effort has been extended to the efficient cancer therapies, the drug resistance is still a major obstacle in cancer chemotherapeutic treatments. Almost 90% of the cancer therapy failure is caused by the relative problems. Recently, the application of drug coated polymer nanospheres and nanoparticles to inhibit the related drug resistance has attracted much attention. In this report, we have explored a novel strategy to inhibit the multidrug resistance of the targeted tumor cells by combining the unique properties of tetraheptylammonium capped Fe(3)O(4) magnetic nanoparticles with the drug accumulation of anticancer drug daunorubicin. Our results of confocal fluorescence and atomic force microscopy (AFM) as well as electrochemical studies demonstrate the remarkable synergistic effect of Fe(3)O(4) nanoparticles on drug uptake of daunorubicin in leukemia K562 cells. These observations indicate that the interaction between the magnetic nanoparticles Fe(3)O(4) and biologically active molecules on the membrane of leukemia cell lines may contribute to their beneficial effect on cellular uptake so that the synergistic enhanced effect of magnetic nanoparticles Fe(3)O(4) on drug uptake of drug resistance leukemia K562 cells could be observed upon application of the Fe(3)O(4) nanoparticles.

Doxorubicin-CdS nanoparticles: a potential anticancer agent for enhancing the drug uptake of cancer cells.

A novel strategy of enhancing the drug uptake by cancer cells through the combination of anticancer drug doxorubicin with cadium sulfide (CdS) nanoparticles has been explored by using confocal fluorescence scanning microscopy as well as electrochemical studies, which demonstrates that CdS nanoparticles can readily conjugate with doxorubicin on the targeted cancer cells and facilitate the uptake of drug molecules in the human leukemia K562 cells. Besides, our observations also indicate that the aggregation of the leukemia cells occured when CdS nanoparticles were introduced into the relative target system together with doxorubicin, suggesting that the specific association of CdS nanoparticles with biologically active molecules on the surface of leukemia K562 cells may change some biorecognition or signal transfer pathway among cancer cells. It is suggested that the competitive binding of CdS nanoparticles with accompanying anticancer drug to the membrane of leukemia K562 cells could efficiently prevent the drug release by the drug resistant leukemia cells and thus inhibit the relative multidrug resistance (MDR) of targeted cancer cells.

The in vitro inhibition of multidrug resistance by combined nanoparticulate titanium dioxide and UV irradition.

The appearance of drug-resistant (especially, multidrug-resistant (MDR)) tumor cells is a major obstacle to the success of chemotherapy; thus, the development of effective anti-MDR agents plays an important role in the tumor therapy. In this report, the considerable effect of nano-TiO2 and UV illumination on the drug resistance of target cancer cells has been explored, and the fresh evidence from the fluorescence spectroscopy and microscopy as well as electrochemical studies demonstrates the significant enhancement effect of nano-TiO2 to the drug uptake by drug-resistant leukemia cells. Besides, it is also observed that the combination of the nano-TiO2 and UV irradiation with the accompanying anticancer drug daunorubicin could provoke some considerable changes of the cell membrane of the target leukemia cells, which indicates that nano-TiO2 could not only increase the drug accumulation in target cancer cells, but also act as an effective anti-MDR agent to inhibit the relative drug resistance.

Synergistic enhancement effect of magnetic nanoparticles on anticancer drug accumulation in cancer cells.

Three kinds of magnetic nanoparticle, tetraheptylammonium capped nanoparticles of Fe(3)O(4), Fe(2)O(3) and Ni have been synthesized, and the synergistic effect of these nanoparticles on the drug accumulation of the anticancer drug daunorubicin in leukaemia cells has been explored. Our observations indicate that the enhancement effect of Fe(3)O(4) nanoparticles is much stronger than that of Fe(2)O(3) and Ni nanoparticles, suggesting that nanoparticle surface chemistry and size as well as the unique properties of the magnetic nanoparticles themselves may contribute to the synergistic enhanced effect of the drug uptake of targeted cancer cells.

MDR reversal activity of bromotetrandrine in vitro and in vivo.

The present study was aimed to evaluate the MDR reversal activity of bromotetrandrine (BrTet) in vitro and in vivo. The inhibitory effects of adriamycin (ADM) used alone or in combination with BrTet or Tet on the proliferation of K562 and K562/A02 cells were evaluated by MTT assay. The ADM accumulation and the protein levels of P-glycoprotein (P-gp) were detected by flow cytometry. The mRNA levels of P-gp were determined by RT-PCR. The in vivo effect of BrTet and Tet was investigated by using nude mice grafted with sensitive human leukemia cell line K562 and MDR cell line K562/A02. The results showed that BrTet at 0.25, 0.5 and 1 micromol/L reversed the resistance to ADM in MDR K562/A02 cells in a dose-dependent manner. Flow cytometry suggested that BrTet significantly increased the intracellular accumulation of ADM in K562/A02 cells in a dose-dependent manner. BrTet also inhibited the overexpression of P-gp in K562/A02 cells, and down-regulated mdr1 expression. In nude mice bearing K562 xenografts on the left flank and K562/A02 xenografts on the right flank, intraperitoneal injection of 10 mg/kg BrTet significantly enhanced the antitumor activity of ADM against K562/A02 xenografts with inhibitory rates of 26.1%, while ADM alone inhibited the growth of K562/A02 xenografts only by 5.8%. No enhancement effect by BrTet was seen in K562 xenografts. It is concluded that BrTet shows significant MDR reversal activity in vitro and in vivo. Its activity may be related to the inhibition of P-gp overexpression and the increase intracellular accumulation of anticancer drugs. BrTet may be a promising-MDR modulator for eventual assessment in the clinic.

Reversal in multidrug resistance by magnetic nanoparticle of Fe3O4 loaded with adriamycin and tetrandrine in K562/A02 leukemic cells.

Drug resistance is a primary hindrance for efficiency of chemotherapy. To investigate whether Fe3O4-magnetic nanoparticles (Fe3O4-MNPs) loaded with adriamycin (ADM) and tetrandrine (Tet) would play a synergetic reverse role in multidrug resistant cell, we prepared the drug-loaded nanoparticles by mechanical absorption polymerization to act with K562 and one of its resistant cell line K562/A02. The survival of cells which were cultured with these conjugates for 48 h was observed by MTT assay. Using cells under the same condition described before, we took use of fluorescence microscope to measure fluorescence intensity of intracellular ADM at an excitation wavelength of488 nm. P-glycoprotein (P-gp) was analyzed with flow cytometer. The expression ofmdrl mRNA was measured by RT-PCR. The results showed that the growth inhibition efficacy of both the two cells increased with augmenting concentrations of Fe3O4-MNPs which were loaded with drugs. No linear correlation was found between fluorescence intensity of intracellular adriamycin and augmenting concentration of Fe3O4-MNPs. Tet could downregulate the level of mdr-1 gene and decrease the expression of P-gp. Furthermore, Tet polymerized with Fe3O4-MNPs reinforced this downregulation, causing a 100-fold more decrease in mdrl mRNA level, but did not reduce total P-gp content. Our results suggest that Fe3O4-MNPs loaded with ADM or Tet can enhance the effective accumulation of the drugs in K562/A02. We propose that Fe3O4-MNPs loaded with ADM and Tet probably have synergetic effect on reversal in multidrug resistance.

Synergistic effect of the combination of nanoparticulate Fe3O4 and Au with daunomycin on K562/A02 cells.

In this study, we have explored the possibility of the combination of the high reactivity of nano Fe3O4 or Au nanoparticles and daunomycin, one of the most important antitumor drugs in the treatment of acute leukemia clinically, to inhibit MDR of K562/A02 cells. Initially, to determine whether the magnetic nanoparticle Fe3O4 and Au can facilitate the anticancer drug to reverse the resistance of cancer cells, we have explored the cytotoxic effect of daunomycin (DNR) with and without the magnetic nano-Fe3O4 or nano-Au on K562 and K562/A02 cells by MTT assay. Besides, the intracellular DNR concentration and apoptosis of the K562/A02 cells was further investigated by flow cytometry and confocal fluorescence microscopic studies. The MDR1 gene expression of the K562/A02 cells was also studied by RT-PCR method. Our results indicate that 5.0 x 10(-7) M nano-Fe3O4 or 2.0 x 10(-8) M nano-Au is biocompatible and can apparently raise the intracellular DNR accumulation of the K562/A02 cells and increase the apoptosis of tumor cells. Moreover, our observations illustrate that although these two kinds of nanoparticles themselves could not lower the MDRI gene expression of the K562/A02 cells, yet they could degrade the MDR1 gene level when combining with anticancer drug DNR. This raises the possibility to combine the nano-Fe3O4 or nano-Au with DNR to reverse the drug resistance of K562/A02 cells, which could offer a new strategy for the promising efficient chemotherapy of the leukemia patients.

The enhancement effect of gold nanoparticles in drug delivery and as biomarkers of drug-resistant cancer cells.

The enhancement effect of 3-mercaptopropionic acid capped gold nanoparticles (NPs) in drug delivery and as biomarkers of drug-resistant cancer cells has been demonstrated through fluorescence microscopy and electrochemical studies. The results of cell viability experiments and confocal fluorescence microscopy studies illustrate that these functionalized Au NPs could play an important role in efficient drug delivery and biomarking of drug-resistant leukemia K562/ADM cells. This could be explored as a novel strategy to inhibit multidrug resistance in targeted tumor cells and as a sensitive method for the early diagnosis of certain cancers. Our observations also indicate that the interaction between the functionalized Au NPs and biologically active molecules on the surface of leukemia cells may contribute the observed enhancement in cellular drug uptake.

[Preparation of Fe3O4-magnetic nanoparticles loaded with adriamycin and its reversal of multidrug resistance in vitro].

To prepare Fe(3)O(4)-magnetic nanoparticles loaded with adriamycin and investigate the reversal role of drug-loaded nanoparticles in K562 and resistant cell line K562/A02, the drug-loaded nanoparticles were prepared by using mechanical absorption polymerization at different conditions of 4 degrees C or 37 degrees C for 24 or 48 hours. The survival of cells cultured with drug-loaded nanoparticles for 48 hours was detected by MTT assay, then the growth inhibition efficacy of cells was calculated. The results showed that the growth inhibition efficacy of both two cell lines was enhanced with increasing concentration of Fe(3)O(4)-magnetic nanoparticles. The inhibitory ratio of two cell lines obtained at 4 degrees C and for 48 hours was significantly better than that at 37 degrees C and 24 hours. In conclusion, Fe(3)O(4)-magnetic nanoparticles can load adriamycin by using mechanical absorption polymerization, but depended on proper temperature and time. Furthermore, drug-loaded nanoparticles showed an ability reversing multidrug resistance.

[Research advance on SDF-1/CXCR4 axis associated with hematological malignancies: review].

The stromal cell-derived factor 1 (SDF-1) interacts with its receptor CXCR4 to transduction signals, playing important roles in most physiological and pathological processes. It is reported that CXCR4 is highly expressed in many kinds of hematological malignancies and closely related to the prognosis, drug resistance and relapse of diseases. The growth of tumor cells can be inhibited by the anti-SDF-1 antibody or anti- CXCR4 antibody, supporting a new way for the therapy against hematological malignancies. Their expression in relation with prognosis and drug resistance of hematological malignancies are summarized in this review.