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புற்றுநோய் அறிவியல் & சிகிச்சை

ஐ.எஸ்.எஸ்.என்: 1948-5956

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தொகுதி 6, பிரச்சினை 11 (2014)

ஆய்வுக் கட்டுரை

Induction of Nitric Oxide and TNF-Α in Newcastle Disease Virus (NDV) AF2240 Infected RAW 264.7 Macrophages and their Cytotoxic Activity on MDA-MB-231 Breast Cancer Cell Line

Ismaila Ahmed, Umar Ahmad, Yong Yoke Keong, Nizar Abdu Manna and Fauziah Othman

Background: It is well known that Newcastle Disease Virus (NDV) AF2240 has antitumor activity against breast cancer cell lines. Several studies have thought this activity depend on direct viral oncolysis, which may not be the only factor that play a role in the antitumor effect of the virus. However, the mechanism underlying its antitumor effect is largely unresolved. In line with this observation, we postulated that NDV AF2240 may induce an in vitro production of Nitric Oxide (NO) and Tumor Necrosis Factor (TNF-α) in RAW 264.7 macrophages for cytotoxic activity on breast cancer cells.

Methods: NDV AF2240 were subjected to different experimental conditions (Live, UV-inactivated and Heatinactivated), different Heamagglutination (HA) titer of the virus were co-cultured with RAW 264.7 cells to get the cell-free supernatant. Levels of TNF-α, and NO production were measured by ELISA and Griess assay respectively. MTT assay was later used to determine their cytotoxicity on MDA-MB-231 breast cancer cell line in vitro.

Results: NDV was found to be an excellent inducer in RAW 264.7 macrophage cells of TNF-α (P<0.05) and NO production (P<0.05) when compared with the negative control. The supernatant containing NO and TNF-α was also found to be cytotoxic against MDA-MB-231 cells (P<0.05) when compared with the negative control, indicating that viral replication was not necessary for their production, because UV-inactivated NDV for 15 minutes was almost as good as lived NDV. However, heat inactivated NDV did not induce TNF-α and NO production.

Conclusion: This suggests the relevance of TNF-α and NO in the indirect antitumor effect of NDV AF2240, and also shown that mare contact between the macrophages and the NDV is enough to induce TNF-α and NO production in macrophages.

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Combination Treatment with Apricoxib and IL-27 Enhances Inhibition of Epithelial-Mesenchymal Transition in Human Lung Cancer Cells through a STAT1 Dominant Pathway

Mi-Heon Lee, Puja Kachroo, Paul C Pagano, Jane Yanagawa, Gerald Wang, Tonya C Walser, Kostyantyn Krysan, Sherven Sharma, Maie St. John, Steven M Dubinett and Jay M Lee

Background: The cyclooxygenase 2 (COX-2) pathway has been implicated in the molecular pathogenesis of many malignancies, including lung cancer. Apricoxib, a selective COX-2 inhibitor, has been described to inhibit epithelial-mesenchymal transition (EMT) in human malignancies. The mechanism by which apricoxib may alter the tumor microenvironment by affecting EMT through other important signaling pathways is poorly defined. IL-27 has been shown to have anti-tumor activity and our recent study showed that IL-27 inhibited EMT through a STAT1 dominant pathway.

Objective: The purpose of this study is to investigate the role of apricoxib combined with IL-27 in inhibiting lung carcinogenesis by modulation of EMT through STAT signaling.

Methods and Results: Western blot analysis revealed that IL-27 stimulation of human non-small cell lung cancer (NSCLC) cell lines results in STAT1 and STAT3 activation, decreased Snail protein and mesenchymal markers (N-cadherin and vimentin) and a concomitant increase in expression of epithelial markers (E-cadherin, β-and γ-catenins), and inhibition of cell migration. The combination of apricoxib and IL-27 resulted in augmentation of STAT1 activation. However, IL-27 mediated STAT3 activation was decreased by the addition of apricoxib. STAT1 siRNA was used to determine the involvement of STAT1 pathway in the enhanced inhibition of EMT and cell migration by the combined IL-27 and apricoxib treatment. Pretreatment of cells with STAT1 siRNA inhibited the effect of combined IL-27 and apricoxib in the activation of STAT1 and STAT3. In addition, the augmented expression of epithelial markers, decreased expression mesenchymal markers, and inhibited cell migration by the combination treatment were also inhibited by STAT1 siRNA, suggesting that the STAT1 pathway is important in the enhanced effect from the combination treatment.

Conclusion: Combined apricoxib and IL-27 has an enhanced effect in inhibition of epithelial-mesenchymal transition and cell migration in human lung cancer cells through a STAT1 dominant pathway.

கட்டுரையை பரிசீலி

Angio-Inhibitors in Ovarian Cancer

Nikos G Gavalas, Sofia-Paraskevi Trachana, Meletios A Dimopoulos and Aristotle Bamias

Ovarian Cancer represents the most fatal type of gynaecological malignancies. The tumor microenvironment consists the region where a number of processes contributing to the pathogenesis of this deadly disease occur. Except the cell proliferation process itself, processes such as angiogenesis can be held accountable for the progress of disease. More specifically, angiogenesis represents a hallmark phenomenon in cancer and a number of studies have shown that it is responsible for the spread of tumor and metastasis in most types of cancer including ovarian cancer. The process leads to new blood vessel formation and stabilization of the tumor vasculature. In recent years angiogenesis has been given considerable attention in order to identify novel targets for developing effective antitumor therapies. Among other families of molecules, growth factors have been identified to play important roles in driving the process of angiogenesis and thus the formation of new blood vessels that play the key role in supplying cancer with appropriate nutrients, hence allowing its spread and metastasis. Such molecules include the vascular endothelial growth factor (VEGF), the platelet derived growth factor (PDGF), the fibroblast growth factor (FGF) and the angiopoietin (Ang)/Tie 2 receptor complex. These proteins are key players in molecular pathways located within the tumor cell and they have been recently under heavy research being in the spotlight of the development of anti angiogenic molecules that may act as stand-alone therapeutics (monotherapy) or in combination with current treatment regimes such as standard chemotherapy. Such molecules include Bevacizumab, Sorafenib, Imatinib mesylate, Sunitinib, Trebananib, Aflibercept, Intedanib, Pazopanib, and Cediranib. There is also a special reference to the possible angio-agenic effect that paclitaxel may confer either in monotherapy or in combination with other agents. The roles of these molecules that have been developed in order to combat angiogenesis are described in this paper.

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Genetic and Computational Analysis of Tgfb1 & Fgfr2 Polymorphism in Correlation to Breast Cancer Susceptibility in Pakistani Women

Uzma Shaukat, Mehwish Toor, Bilal Ahmad, Sahar Fazal and Nasir Mehmood

Worldwide genome-wide association studies have proven very helpful in analyzing the association of susceptible breast cancer genes. In the study presenting here association of susceptible genes FGFR2 and TGFB1 to breast cancer development was explored in Pakistani population which will be helpful in determining the choice of therapy and genetic counseling for ultimately cure of the disease and better treatment. The outcome is that we analyzed 100 samples including follow up patients and found that T-C base substitution of FGFR2 rs1219648 and rs2981582 was strongly associated with the risk of breast cancer whereas the T-C base substitution of TGFB1 rs1800470 was found in some cases though not in all patients suggesting its association within specific caste Awan and Rajput belonging to Mianwali and Khushab district area and thereby elucidating weak association with breast cancer risk. In follow ups we have analyzed that patient with T nucleotide at base position 88 had showed no therapeutic response to chemotherapy i.e. taxanestamoxifen, whereas individuals with C nucleotide chemotherapy was effective. In Silico analysis revealed that mutations of FGFR2 are in intronic region. We subsequently scanned its intronic region. We subsequently scanned its intronic region and mutant structure comparison of TGFB1 with native showed drastic change in its structure having stemmed –loop which blocks the receptor site. Detailed medical history of patients revealed that in our population breast cancer is strongly associated with risk factors such as post menopause, high tea consumption and same caste of spouse and previous breast biopsy. Statistical analysis showed that the frequency of breast cancer at age greater than 40 is higher. It has also been seen that women who had children after age 30 were more susceptible to breast cancer. P value was greater than 0.1 which is not significant showing its high prevalence in our society similar to western population. Phylogenetic analysis has also been done on both genes. In FGFR2 mouse and humans are in same clusters showing close relation whereas in TGFB1 horse and chimpanzee show convergence to human. This analysis will help in choice of economical organism for pharmacogenomics to check drug response.

கட்டுரையை பரிசீலி

Angiogenesis in Head and Neck Cancer

Merlano MC, Russi EG and Denaro N

Locally advanced Head and Neck Squamous Cell Carcinoma (HNC) is a challenging disease for the lack of effective therapies even in the era of molecular medicine (the five-year survival does not exceed 40%). For patients with metastatic and recurrent HNC the standard treatment is the combination of Cetuximab/Platinum and Fluorouracil but median overall survival rate for this population remains lower than 11%. The main reasons of these disappointing outcomes include acquired drug resistance, anti Epidermal growth factors variants, epithelial to mesenchymal transition and tumor hypoxia.

Angiogenesis plays a crucial role in HNSCC development and proliferation. Drugs may interfere with the angiogenic process via different mechanisms and there is a sound rationale for combining anti-angiogenic agents with chemotherapy or multiple anti-angiogenic strategies. Promising preclinical results with angiogenic inhibitors have engendered a number of trials, but until now there are not yet conclusive data on the value of anti-angiogenic therapy in HNC.

This paper aims to review the role of angiogenesis inhibitors in head and neck cancer.

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Depletion of RUVBL2 in Human Cells Confers Moderate Sensitivity to Anticancer Agents

Mayumi Miyamoto-Matsubara, Yi Han, Koji Ono, Ming-Zhang Xie, Amir MH Salem, Mahmoud I Shoulkamy, Toshiaki Nakano and Hiroshi Ide

Background: Many anticancer agents kill cancer cells by inducing lethal damage in DNA, but the capacity of DNA repair of cells reduce the therapeutic efficacy of anticancer agents. RuvB-like (RUVBL) 2 is part of large protein complexes such as TIP60 and INO80 that are involved in chromatin remodeling and DNA damage responses and repair. Relatively few studies have investigated the role of RUVBL2 in the survival of cells after exposure to anticancer agents.

Methods: We depleted RUVBL2 in human MRC5-SV cells by small interfering (si) RNA and assessed the sensitivity of the cells to chemotherapeutic anticancer agents including cisplatin (cisPt), 2’-deoxy-5-azacytidine (azadC), and mitomycin C (MMC), and to physical DNA-damaging agents including X-rays.

Results: The knockdown efficiency with 10 nM siRUVBL2 was 80% on day 3 post-transfection, and knockdown (>65%) persisted on day 6. The cell growth slowed significantly due to depletion of RUVBL2 when compared to mock- and control siRNA-treated cells, indicating that RUVBL2 is essential for the proliferation of cells. The RUVBL2-depleted cells were moderately sensitive to cisPt, azadC, and X-rays. The increase in the sensitivity to MMC was marginal.

Conclusion: Depletion of RUVBL2 in cells confers moderate sensitivity to anticancer agents and X-rays, presumably through partial impairment of the homologous recombination repair of DNA double-strand break intermediates formed directly or indirectly by anticancer agents or X-rays. Further studies are necessary to clarify the exact role of RUVBL2 in this process.

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Ritonavir: A Powerful Boosting Agent for Overcoming Drug Resistance in Cancer Chemotherapy

Ramya Krishna Vadlapatla, Dhananjay Pal, Aswani Dutt Vadlapudi and Ashim K Mitra

Purpose: A major impediment to successful drug therapy is the development of multidrug resistance (MDR). Drug resistance in HIV patients is also well known. The introduction of highly active antiretroviral therapy (HAART) has substantially reduced HIV resistance and fatalities. It appears that ritonavir along with another protease inhibitor regulates both drug efflux and metabolism to overcome resistance. Therefore, we have examined a similar strategy of combining ritonavir with anticancer drugs to modulate drug efflux, metabolism and allow sufficient drug entry into tumor cells.

Methods: Cells were treated for 72 hours with anticancer drugs alone and in the presence of ritonavir. Quantitative gene expression studies, immunoblot analysis, radioactive uptake studies and Vivid™ fluorescent assay were performed on human colon adenocarcinoma cells (LS180) cells. Cell proliferation, migration and apoptosis assays were performed on human breast adenocarcinoma (T47D) cells and prostate cancer (PC-3) cells.

Results: The overexpression of efflux transporters and metabolizing enzymes was diminished when cells were co-treated with ritonavir. [3H] Lopinavir uptake and VIVID™ assay further confirmed the functional activity of transcribed genes upon co-treatment. When the anticancer agent (doxorubicin, paclitaxel, tamoxifen or vinblastine) was combined with ritonavir, a significantly diminished cell proliferation and migration and augmented caspase activity leading to apoptosis was observed in T47D and PC-3 cells.

Conclusions: Combination therapy of anticancer drug with ritonavir may overcome drug resistance by deactivating the overexpression of efflux transporters and metabolizing enzymes. Therefore, drug regimens containing ritonavir would enhance therapeutic exposure of cancer cells to anticancer agents, potentially improving chemotherapeutic efficacy and consequently devoid of resistance.

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