Systemic delivery of siRNA nanoparticles targeting RRM2 suppresses head and neck tumor growth

Systemic delivery of siRNA to solid tumors remains challenging. In this study, we investigated the systemic delivery of a siRNA nanoparticle targeting ribonucleotide reductase subunit M2 (RRM2), and evaluated its intratumoral kinetics, efficacy and mechanism of action. Knockdown of RRM2 by an RNAi mechanism strongly inhibited cell growth in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. In a mouse xenograft model of HNSCC, a single intravenous injection led to the accumulation of intact nanoparticles in the tumor that disassembled over a period of at least 3 days, leading to target gene knockdown lasting at least 10 days. A four-dose schedule of siRNA nanoparticle delivering RRM2 siRNA targeted to HNSCC tumors significantly reduced tumor progression by suppressing cell proliferation and inducing apoptosis. These results show promise for the use of RRM2 siRNA-based therapy for HNSCC and possibly NSCLC

Proteasome Inhibitors Block DNA Repair and Radiosensitize Non-Small Cell Lung Cancer

Despite optimal radiation therapy (RT), chemotherapy and/or surgery, a majority of patients with locally advanced non-small cell lung cancer (NSCLC) fail treatment. To identify novel gene targets for improved tumor control, we performed whole genome RNAi screens to identify knockdowns that most reproducibly increase NSCLC cytotoxicity. These screens identified several proteasome subunits among top hits, including the topmost hit PSMA1, a component of the core 20 S proteasome. Radiation and proteasome inhibition showed synergistic effects. Proteasome inhibition resulted in an 80–90% decrease in homologous recombination (HR), a 50% decrease in expression of NF-κB-inducible HR genes BRCA1 and FANCD2, and a reduction of BRCA1, FANCD2 and RAD51 ionizing radiation-induced foci. IκBα RNAi knockdown rescued NSCLC radioresistance. Irradiation of mice with NCI-H460 xenografts after inducible PSMA1 shRNA knockdown markedly increased murine survival compared to either treatment alone. Proteasome inhibition is a promising strategy for NSCLC radiosensitization via inhibition of NF-κB-mediated expression of Fanconi Anemia/HR DNA repair genes.American Society for Radiation Oncology (Junior Faculty Career Research Training Award)Harvard University. Joint Center for Radiation Therapy (Foundation Grant)Dana-Farber/Harvard Cancer Center (SPORE Developmental Research Project Award in Lung Cancer Research)National Cancer Institute (U.S.) (Award K08CA172354

Curcumin Prevents Palmitoylation of Integrin β4 in Breast Cancer Cells

We thank Dr. Tak yee Aw for technical assistance and critical discussion of the manuscript. This study is supported by American Cancer Society (RSG-09-091-01-CSM: JC) and NIH-NCI (R01CA163657-01A1: JC).Curcumin has been shown to mitigate cancer phenotypes such as invasive migration, proliferation, and survival by disrupting numerous signaling pathways. Our previous studies showed that curcumin inhibits integrin β4 (ITG β4)-dependent migration by blocking interaction of this integrin with growth factor receptors in lipid rafts. In the current study, we investigated the possibility that curcumin inhibits ITG β4 palmitoylation, a post-translational modification required for its lipid raft localization and signaling activity. We found that the levels of ITG β4 palmitoylation correlated with the invasive potential of breast cancer cells, and that curcumin effectively reduced the levels of ITG β4 palmitoylation in invasive breast cancer cells. Through studies of ITG β4 palmitoylation kinetics, we concluded curcumin suppressed palmitoylation independent of growth factor-induced phosphorylation of key ITG β4 Ser and Tyr residues. Rather, curcumin blocked autoacylation of the palmitoyl acyltransferase DHHC3 that is responsible for ITG β4 palmitoylation. Moreover, these data reveal that curcumin is able to prevent the palmitoylation of a subset of proteins, but not indiscriminately bind to and block all cysteines from modifications. Our studies reveal a novel paradigm for curcumin to account for much of its biological activity, and specifically, how it is able to suppress the signaling function of ITG β4 in breast cancer cells.Yeshttp://www.plosone.org/static/editorial#pee

Sistem Pendukung Keputusan Pemilihan Karyawan Terbaik pada PT. Citra Prima Batara dengan Metode AHP

Sistem Pendukung Keputusan Pemilihan Karyawan Terbaik dengan Metode Analytical Hierarchy Process. Penghargaan yang diberikan oleh Perusahaan kepada karyawan terbaiknya dapat mendorong setiap karyawan untuk selalu memberikan kinerja yang terbaik bagi Perusahaan dalam melaksanakan tugas dan kewajibanya di Perusahaan. Pengambilan keputusan untuk menentukan karyawan terbaik dapat dilakukan Perusahaan dengan cara menilai kinerja yang telah dilakukan oleh karyawannya dalam jangka waktu tertentu. Penilaian kinerja karyawan di pada PT. Citra Prima Batara dipengaruhi oleh beberapa kriteria yaitu perilaku kerja, disiplin kerja, kualitas kerja, tanggung jawab kerja, kehadiran, kejujuran. Sistem pendukung keputusan pemilihan karyawan terbaik menggunan metode Analytical Hierarchy Process (AHP), dimana proses pengambilan keputusan dilakukan dengan menilai alternatif pilihan berdasarkan kriteria yang telah ditetapkan. Perhitungan dari metode AHP memberikan hasil yaitu urutan tingkat kepentingan kriteria dan rekomendasi karyawan terbaik, dimana urutan kriteria yang paling penting dimulai dari kejujuran, tanggung jawab kerja, kehadiran, kualitas kerja, perilaku kerja, dan disiplin kerja. Perhitungan matriks alternatif menghasilkan nilai 35,3% untuk Bapak Rega, 22,1% untuk Ibu Dian, 14,4% untuk Bapak Sean, 14,2% untuk Bapak Henky, dan 14% untuk Ibu Febri dan karyawan yang direkomendasikan sebagai karyawan terbaik untuk PT. Citra Prima Batara adalah karyawan dengan memiliki nilai tertinggi yaitu Bapak Rega

Cancer prevention with natural compounds

Botanical and nutritional compounds have been used for the treatment of cancer throughout history. These compounds also may be useful in the prevention of cancer. Population studies suggest that a reduced risk of cancer is associated with high consumption of vegetables and fruits. Thus, the cancer chemopreventive potential of naturally occurring phytochemicals is of great interest. There are numerous reports of cancer chemopreventive activity of dietary botanicals, including cruciferous vegetables such as cabbage and broccoli, Allium vegetables such as garlic and onion, green tea, Citrus fruits, soybeans, tomatoes, berries, and ginger, as well as medicinal plants. Several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin (from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli), and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemoprevention. Phytochemicals have great potential in cancer prevention because of their safety, low cost, and oral bioavailability. In this review, we discuss potential natural cancer preventive compounds and their mechanisms of action. Semin Oncol 37:258-281. (C) 2010 Published by Elsevier Inc

Curcumin Induces Apoptosis of Upper Aerodigestive Tract Cancer Cells by Targeting Multiple Pathways

<div><p>Curcumin, a natural compound isolated from the Indian spice "Haldi" or "curry powder", has been used for centuries as a traditional remedy for many ailments. Recently, the potential use of curcumin in cancer prevention and therapy urges studies to uncover the molecular mechanisms associated with its anti-tumor effects. In the current manuscript, we investigated the mechanism of curcumin-induced apoptosis in upper aerodigestive tract cancer cell lines and showed that curcumin-induced apoptosis is mediated by the modulation of multiple pathways such as induction of p73, and inhibition of p-AKT and Bcl-2. Treatment of cells with curcumin induced both p53 and the related protein p73 in head and neck and lung cancer cell lines. Inactivation of p73 by dominant negative p73 significantly protected cells from curcumin-induced apoptosis, whereas ablation of p53 by shRNA had no effect. Curcumin treatment also strongly inhibited p-AKT and Bcl-2 and overexpression of constitutively active AKT or Bcl-2 significantly inhibited curcumin-induced apoptosis. Taken together, our findings suggest that curcumin-induced apoptosis is mediated via activating tumor suppressor p73 and inhibiting p-AKT and Bcl-2.</p></div

Curcumin induces p73-dependent apoptosis.

<p>(A) Tu212 (left) and H1299 (right) cells were treated with curcumin and expression of p73 and p73β were measured by Western blotting. (B-C) p73 was inactivated in H1299 (B) and 041 (C) cells by dominant negative p73 and apoptosis was measured by annexin V-PE staining. (D) H1299 cells expressing empty vector or dominant negative p73 were treated with curcumin. Whole cell lysates were immunoblotted with PARP and caspase 3 antibodies. For B and C, average results from three independent experiments were plotted with standard deviation as error bars. p values were determined by student t-test. p<0.05 was considered statistically significant.</p

IC₅₀ values of curcumin.

<p>IC₅₀ values of curcumin.</p

Inhibition of p-AKT is required for curcumin-induced apoptosis.

<p>(A) H1299, (B) Tu212 and (C) Tu686 cells were treated with the indicated concentrations of curcumin for the indicated time and expression of p-AKT, AKT and actin were measured by immunoblotting. (D) Tu212 and Tu686 cells were treated with 10 and 15 μM of curcumin, respectively. Expression of AKT mRNA was measured by qPCR. (E) CA-AKT was overexpressed in Tu686 cells and apoptosis was measured. Average results from three independent experiments were plotted with standard deviation as error bars. p value was determined by student t-test. p<0.05 was considered statistically significant.</p