The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties

Glioblastoma multiform (GBM) is the most common primary glial tumor resulting in very low patient survival despite current extensive therapeutic efforts. Emerging evidence suggests that more effective treatments are required to overcome tumor heterogeneity, drug resistance and a complex tumor-supporting microenvironment. PBI-05204 is a specifically formulated botanical drug consisting of a modified supercritical C02 extract of Nerium oleander that has undergone both phase I and phase II clinical trials in the United States for treatment of patients with a variety of advanced cancers. The present study was designed to investigate the antitumor efficacy of this botanical drug against glioblastoma using both in vitro and in vivo cancer models as well as exploring efficacy against glioblastoma stem cells. All three human GBM cell lines, U87MG, U251, and T98G, were inhibited by PBI-05204 in a concentration dependent manner that was characterized by induction of apoptosis as evidenced by increased ANNEXIN V staining and caspase activities. The expression of proteins associated with both Akt and mTOR pathway was suppressed by PBI-05240 in all treated human GBM cell lines. PBI-05204 significantly suppressed U87 spheroid formation and the expression of important stem cell markers such as SOX2, CD44, and CXCR4. Oral administration of PBI-05204 resulted in a dose-dependent inhibition of U87MG, U251, and T98G xenograft growth. Additionally, PBI-05204–treated mice carrying U87-Luc cells as an orthotropic model exhibited significantly delayed onset of tumor proliferation and significantly increased overall survival. Immunohistochemical staining of xenograft derived tumor sections revealed dose-dependent declines in expression of Ki67 and CD31 positive stained cells but increased TUNEL staining. PBI-05204 represents a novel therapeutic botanical drug approach for treatment of glioblastoma as demonstrated by significant responses with in vivo tumor models. Both in vitro cell culture and immunohistochemical studies of tumor tissue suggest drug induction of tumor cell apoptosis and inhibition of PI3k/mTOR pathways as well as cancer stemness. Given the fact that PBI-05204 has already been examined in phase I and II clinical trials for cancer patients, its efficacy when combined with standard of care chemotherapy and radiotherapy should be explored in future clinical trials of this difficult to treat brain cancer

Early diagnosis of prostatic carcinoma may be achieved through in vitro culture of tumor cells harvested by prostatic massage.

Purpose: We documented the results of high energy transurethral microwave thermotherapy in the treatment of benign prostatic hyperplasia. Materials and Methods: We evaluated 116 patients following transurethral microwave thermotherapy according to symptom scores, transrectal ultrasound, free voiding and pressure-flow study parameters. Results: Significant improvement was noted in all objective and subjective parameters. Moreover, cavities in the prostatic urethra were observed in almost 40 percent of the patients. Conclusions: High energy transurethral microwave thermotherapy is an effective therapy for benign prostatic hyperplasia. Patients with larger prostates and moderate to severe bladder outlet obstruction seem to be the best candidates for this higher energy thermotherapy protocol, although morbidity is increased

IL-2-activated rat NK cells express inducible nitric oxide synthase that contributes to cytotoxic function and IFN-g production

Natural killer (NK) cells are large granular lymphocytes capable of destroying cells infected by virus or bacteria and susceptible tumor cells without prior sensitization and restriction by major histocompatability complex (MHC) antigens, Their cytotoxic activity could be strongly enhanced by interleukin-2 (IL-2), Previous findings, even if obtained with indirect experimental approaches, have suggested a possible involvement of the inducible nitric oxide (iNOS) pathway in the NK-mediated target cell killing. The aim of the present study was first to directly examine the induction of iNOS in IL-2-activated rat NK cells isolated from peripheral blood (PB-NK) or spleen (S-NK), and second to investigate the involvement of the iNOS-derived NO in the cytotoxic function of these cells. Our findings clearly indicate the induction of iNOS expression in IL-2-activated PB-NK and S-NK cells, as evaluated either at mRNA and protein levels. Accordingly, significantly high levels of iNOS activity were shown, as detected by the L-arginine to L-citrulline conversion in appropriate assay conditions. The consequent NO generation appears to partially account for NK cell-mediated DNA fragmentation and lysis of sensitive tumor target cells, In fact, functional inhibition of iNOS through specific inhibitors, as well as the almost complete abrogation of its expression through a specific iNOS mRNA oligodeoxynucleotide antisense, significantly reduced the lytic activity of IL-2-activated NK cells. Moreover, IL-2-induced interferon-gamma production appears also to be dependent at least in part, on iNOS induction, (C) 1999 by The American Society of Hematolog

Erk-dependent cytosolic phospholipase activity is induced by cd95 ligand cross-linking in the mouse derived Sertoli cell line TM4 and is required to trigger apoptosis in CD95 bearing cells

In the present study we demonstrated that CD95L crosslinking generated reverse signalling in the mouse derived Sertoli cell line TM4, Treatment of TM4 cells with mAb anti-CD95L induced activation of the cytosolic phospholipase A(2) (cPLA(2)), Cytosolic PLA, activation was controlled by the MAPK pathway as indicated by the ability of the specific MEK inhibitor, PD098059, to abolish cPLA2 activation, In addition, Western blot experiments showed a rapid increase in phosphorylated Erk1/2 following CD95L cross-linking, while no effect on the phosphorylation of other MAPK, p38 or JNK, was observed, CD95L cross-linking by mAb increased the levels of soluble CD95L and apoptotic activity of TM4 cell supernatants, which was blacked by co-incubation with the PLA, inhibitor, AACOCF3 or PD098059, Finally, pre-treatment of TM4 cells with AACOCF(3) or PD098059 completely abolished TM4-induced apoptosis of Jurkat T cells, thus indicating that the Erk/cPLA(2) pathway is required for CD95L-induced apoptosis

The TORC1/TORC2 inhibitor, Palomid 529, reduces tumor growth and sensitizes to docetaxel and cisplatin in aggressive and hormone-refractory prostate cancer cells.

One of the major obstacles in the treatment of hormone-refractory prostate cancer (HRPC) is the development of chemo-resistant tumors. The aim of this study is to evaluate the role of Palomid 529 (P529), a novelTORC1/TORC2 inhibitor, in association with docetaxel (DTX) and cisplatin (CP). This work utilizes a wide panel of prostatic cancer cell lines with or without basal activation of Akt as well as two in vivo models of aggressive HRPC. The blockade of Akt/mTOR activity was associated to reduced cell proliferation and induction of apoptosis. Comparison of IC50 values calculated for PTEN-positive and PTEN-negative cell lines as well as the PTEN transfection in PC3 cells or PTEN silencing in DU145 cells revealed that absence of PTEN was indicative for a better activity of the drug. In addition, P529 synergized with DTX and CP. The strongest synergism was achieved when prostate cancer (PCa) cells were sequentially exposed to CP or DTX followed by treatment with P529. Treatment with P529 before the exposure to chemotherapeutic drugs resulted in a moderate synergism, whereas intermediated values of combination index were found when drugs were administered simultaneously. In vivo treatment of a combination of P529 with DTX or CP increased the percentage of complete responses and reduced the number of mice with tumor progression. Our results provide a rationale for combinatorial treatment using conventional chemotherapy and a Akt/mTOR inhibitor as promising therapeutic approach for the treatment of HRPC, a disease largely resistant to conventional therapies. © 2011 Society for Endocrinology