Radiotherapy (RT) is a common treatment for localised prostate cancer, but can cause important side effects. The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival. This would elicit a similar therapeutic response using lower doses of RT and, in turn, reducing side effects. This study describes the antitumour activity of the novel Akt inhibitor 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529 or P529) as well as its ability to decrease radiation-activated phospho-Akt (p-Akt) signalling in a prostate cancer model. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (GI50) o35 mM. In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg À1 P529 or 6 Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining). Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer.

BackgroundThere is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC).MethodsWe selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed in vitro. In vivo experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out.ResultsLapatinib dramatically reduced cell proliferation (P < 0.0001), DNA synthesis (P < 0.006), and colony formation capacity (P < 0.0001) in A549 cells in vitro. Furthermore, lapatinib induced G1 cell cycle arrest (P < 0.0001) and apoptotic cell death (P < 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. In vivo experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (P < 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (P < 0.0001).ConclusionOverall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.

Our results support the use of Sunitinib in prostate cancer and shows that both hypoxia and cancer stem cells are involved in the effect elicited by this drug. Combination of Sunitinib with radiotherapy warrants further consideration to reduce prostate cancer burden.

Prostate cancer (PrCa) is the most common malignancy and the second leading cause of cancer death in men. Although localized PrCa can be successfully cured, advanced hormone refractory tumors are resistant to current therapeutic regimes. Therefore, novel approaches for effective malignancy control are still required. Molecular targeted therapies have emerged as promising alternatives to classical chemo/radiotherapy. The clinical benefit of the multi-tyrosine kinase inhibitor Sunitinib, which blocks the activity of receptors such as PDGFR, VEGFR1/2, FLT3, and c-KIT has been proven in renal carcinoma, GIST, and neuroblastoma. In this work, we have tested the therapeutical efficacy of sunitinib against PrCa both in vitro and in vivo, using the androgen-independent cell line PC-3. These cells express target receptors PDGFRa/b, and VEGFR1/2. Sunitinib dramatically reduced cell proliferation in vitro (P&lt;0.0001) in a dose-dependent manner (with an IC50 of 1-2 micro-M) and colony formation (P&lt;0.0001), through an autocrine mechanism. Moreover, when combined with doses of 2 and 4 Gy ionizing radiation, sunitinib enhanced the inhibitory activity of radiotherapy in colony formation assays. In vivo experiments revealed that PC3 tumor-bearing mice treated with 80 mg/Kg/day sunitinib had significantly smaller tumors (63% reduction) than controls. A single dose of 6 Gy caused tumor shrinkage by 80%, whereas the combination of both therapies resulted in more than 90% tumor reduction, suggesting that sunitinib could be used as a radiosensitizer. Positron emission tomography (PET) analyses with 18-FDG, FMISO, and FLT tracers showed a decrease in glucose uptake, hypoxia, and cell proliferation, respectively, in sunitinib-treated mice, as compared to controls. Immunohistochemical analysis for CD-31 revealed an expected reduction in tumor angiogenesis in sunitinib-treated tumors in comparison with untreated tumors. Overall, these data support the use of sunitinib as a clinically relevant drug for the treatment of PrCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3621.

Parvimonas Micra is an anaerobic gram-positive coccus, usually found in the human oral mucosa. We present a case of cerebral abscess provoked by Parvimonas Micra, an infrequent agent for this pathology, in an 85-year-old immunocompetent man with progressive onset left hemiparesis. The diagnosis was realized through the computed tomography and magnetic resonance imaging. Surgical options are aspiration or total removal of the abscess. Each of the options has associated advantages and disadvantages. In our case we decided to perform a craniotomy to the drainage of the pus and the removal of the capsule from the abscess. After the neurosurgical intervention and collection of purulent contents, the pathologic microorganism could be identified. For complement the treatment, antibiotics were administered. The patient's clinic clearly improved after the surgical and medical management, complemented by motor rehabilitation plan. The treatments applied to this patient were effective, with a progressively favorable evolution of the clinical status.