Day 3 :
- Track 7: Carcinogenesis and Mutagenesis and OMICS in Cancer Research
Track 8: Anti-Cancer Drug Discovery and Development
Track 9: Cancer and tumor immunobiology, cancer immunotherapy and stem cell therapy
Track 10: Economic impact of cancer
New York Medical College, USA
Texas State University, USA
Veronica J James completed her PhD in Physics from the University of NSW in 1971. Working in crystallography, she published 40 papers on the molecular structures of small organic crystals, before moving into the fi bre diffraction studies of collagen and keratin. In this area she has carried out the diffraction study that produced the successful structure for hard α-keratin and also pioneered the fi bre diffraction diagnostic tests for breast, colon, prostate cancers and for Alzheimer’s Disease. She was awarded an OAM for her Phones for the Deaf Program and her Advanced Physics Programs in 1996.
I have a dream of a future without mammograms for women or prostate biopsies and PSA tests for men. What good are tests with such low success scores? Standing in the wings are tests with 100% accuracy for the diagnosis of breast cancer and prostate cancer. Th e fi bre diff raction test of hair for breast cancer has three advantages over mammograms: Hair sample is cut close to the skin – no pain. Tests are suitable for all ages No irradiation of breast is needed A positive breast cancer diagnosis appears earlier than by any other test Following successful surgery, a further test reveals the breast cancer change has gone thus no worrying for 15 years Hair samples also reveal the presence of Alzheimer’s disease before the brain is altered, thus allowing time for suitable medication to be used Th e skin biopsy diff raction test for prostate cancer also off ers similar advantages: Skin biopsies are taken from areas remote from the prostate. Th is eliminates infection problems associated with the prostate biopsies Th e prostate cancer diagnosis is 100% accurate but also earlier than any other diagnostic test High and low grade prostate cancers can be diagnosed and any invasions can be identifi ed as perineural and lymphatic types Following successful treatment the prostate cancer change disappears: No need to worry Breast cancer and prostate cancer tests are ready to go at the moment. Th ey should be in use, not in dreams
St. Petersburg State University, Russia
Time : 08:20-08:40
Alexander Shavva was Head of unique Department of Natural Chemistry Department at Saint-Petersburg State University during 25 years (988-2014). He is Founder of steroid scientifi c direction in 1975. He has published more than 4 5+ patents and 120+articles. He was member of International Scientifi c Commissions and Head of Projects with big Pharmaceutical Firms.
Breast cancer (BC) is one of the most wide spread oncological diseases, and very oft en is estrogen-sensitive. Aromatase, 17β-hydroxysteroid dehydrogenase (HSD) and estrone sulfatase (ES) are considered as suitable targets for the treatment of hormone-sensitive oncological diseases. New inhibitors of these enzymes based on estrogen sulfamates are of special interest, not least of all due to possibility for development of dual inhibitors of ES and aromatase or ES and 17β-HSD. Such inhibitors also may play important role in the regulation of metabolic processes in prostate cancer. Almost all known steroid sulfamates have natural skeleton, despite the fact that products of their hydrolysis should not have hormonal activity. We synthesized sulfamates of 8α-steroid estrogen analogues and investigated perspectives of their use as inhibitors of BC cell growth, since their metabolism is diff erent from metabolism of natural steroids. Additionally, some modifi cations in 8α-steroid skeleton may be introduced easier. We showed that 7β-methyl-6-oxa-D-homo-8α-estronesulfamate (1) is perspective ES inhibitor, and the product of its hydrolysis, 7β-methyl-6-oxa-D-homo-8α-estrone (2) has no hormonal activity. Docking of steroid 2 intoα- ERLBD showed that crucial role in dramatic decreasing of uterotropic activity belongs to β-methyl group at С-7, that became the reason for preparation of various 7β-methyl- steroids. Synthesized steroids 3 and 4 fully block the growth of BC MCF-7 cell lines at the concentration 20 γ/ml, and do not aff ect the normal human skin fi broblast cell line growth. Finally, we found 5 steroids with activity against BC cells as has clinical standard tamoxifen. Th is important fi nding opens the new strategy for investigation of anti-cancer activity of such analogues in combination with medications having another mechanism of action.
CNRS University of Lyon, France
Title: Selective modulators of resistant cancer cells overexpressing ABC transporters: Drug-effl ux inhibitors and apoptosis inducers
Time : 08:40-09:00
Attilio Di Pietro is heading a group entitled “Drug resistance mechanism and modulation” at the Institute of Protein Biology and Chemistry (IBCP) of Lyon, supported by the National Center for Scientifi c Research (CNRS) and the University of Lyon. He got a Doctorat d’Etat ès-Sciences from the University of Lyon, at Villeurbanne in 1981, on mitochondrial bioenergetics, and spent a Post-doctoral training with Prof. André Goffeau at the University of Louvain-La-Neuve, Belgium, in 1982-83 on yeast plasma membrane transporters. He became independent in 1992 in studying membrane ATP-binding cassette (ABC) transporters involved in multidrug resistance, especially in cancercells. He chaired a Gordon Research Conference on “Multidrug Effl ux Systems” in Oxford, UK, in August 2005, and is organizing the annual French-Belgian meeting on ABC transporters since 2006. He has published around 140 papers in international journals, and deposited several patents. He has given around 70 invited talks to international meetings in the fi elds of drug discovery and mechanism of cancer cell multidrug resistance. In 2009, his group got Certifi cation by the French National League against Cancer.
Multidrug ABC (“ATP-binding cassette”) transporters are involved, upon overexpression, in chemoresistant tumors by pumping anticancer drugs out of the cells. For early discovered ABCB1/“Pglycoprotein”, third-generation drug-effl ux inhibitors are under clinical development. For more recently identifi ed ABCG2/“breast cancer resistance protein”, we have screened diff erent series of fl avonoids and derivatives, such as fl avones, rotenoids and acridones, and more recently chalcones and chromones, as inhibitors of mitoxantrone effl ux from transfected HEK293 human cells and as chemosensitizers of cell proliferation, to establish 3D-Quantitative Structure-Activity Relationships. Two types of selective, non-competitive, inhibitors have been characterized, either inhibiting or stimulating the basal ATPase activity. Th e most potent inhibitoris indeed effi cient in vivo on SCID mice, xenograft ed with human ABCG2-transfected cells, by chemosensitizing tumor growth to the drugsubstrate irinotecan. Th ese selective inhibitors constitute good drug candidates, with low intrinsic toxicity, as sensitizers of cell proliferation to conventional chemotherapeutics. Th e “Multidrug Resistance Protein 1” ABCC1 is able to catalyze the effl ux of either glutathione conjugates or free glutathione together with hydrophobic substrate drugs. We have identifi ed modulators such as verapamil mimicking substrates and inducing a fast and massive effl ux of intracellular glutathione from ABCC1- overexpressing cells, leading to a selective cell death through apoptosis, due to “collateral sensitivity”, or hypersensitivity. Th e overexpressed transporter then constitutes the Achilles’ heel of such resistant cancer cells. Since verapamil is known for its cadiotoxic eff ects, we investigated other types of modulators such as xanthones, fl avones and fl avonoid dimers. Glutathione effl ux appeared to be necessary, but not suffi cient alone, to trigger apoptosis, indicating the contribution of other partner(s) or signaling pathway(s). Such apoptosis inducers may constitute a new type of anticancer drugs operating through an original strategy aimed at selectively targeting and eliminating multidrug-resistant tumors overexpressing the ABCC1 transporter.
Universidade de Lisboa, Portugal
Title: Ruthenium-based anti-cancer compounds: Insights into their uptake mechanisms and cellular targets
Time : 09:00-09:20
Fernanda Marques is graduated in Chemical Engineering from Instituto Superior Técnico, Universidade de Lisboa and has a PhD in Biochemistry from Faculdade de Ciências, Universidade de Lisboa. She is a Scientifi c Researcher at Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, a Nuclear Tecnological Institute for Research. During the last ten years, she has been involved in the biological evaluation of (radio)metal-based compounds as potential therapeutic agents. She has published more than 50 papers in reputed journals.
Ruthenium compounds have shown highly promising anticancer activity and may provide a less toxic and more eff ective alternatives to platinum-based chemotherapies. Many diff erent ruthenium compounds have been tested for their anticancer properties, however without enough investigation into their mode of action. With the aim to give a contribution to elucidate their mechanism of action we studied a set of structurally related Ru(5-C5H5) complexes with bidentate N,N´-heteroaromatic ligands as prospective metallodrugs, with focus on exploring the uptake, cell death mechanisms and potential cellular targets. Th ese complexes enter the cells by a temperature-dependent process, probably facilitated by binding to plasma transferrin, present high anti proliferative effi cacy in a broad range of tumor cells, preferential localization at the cell membrane and cytosol and the ability to inhibit a lysosomal enzyme, acid phosphatase, in a dose-dependent mode. We have extended these studies to examine the potential of these complexes to target cancer cell metabolism, the energetic-related phenotype of cancer cells. Th e reliance of glycolytic cancer cells on trans-plasma-membrane electron transport (TPMET) systems for their continued survival raises the question of their appropriateness as a target for anticancer drug development strategies. Th e results from this study indicated that these ruthenium complexes can inhibit lactate production and TPMET activity in a way dependent on the cancer cell aggressiveness and the concentration of the complexes. In vivo antitumor activity of these complexes in a prostate tumor animal model is underway.
Palacky University, Czech Republic
Time : 09:20-09:40
Jan Hlavac has completed his PhD in 1997 at Palacký University, Olomouc. Currently he works as the Head of Department of Medicinal Chemistry in Institute of Translational and Medicinal Chemistry in Olomouc. He has published more than 55 papers in reputed journals and is co-author of several patents covering the preparation of novel drugs as well as methods of the specifi c modifi cation of organic substances. His research interests include organic, bioorganic, medicinal and analytical chemistry.
2-Phenyl-3-hydroxy quinolinones (2P3HQs) can be considered as azaanalogues of naturally occurred fl avones known for their wide range of biological activities 2P3HQs exhibited anticancer activity in-vitro against drug sensitive as well as drug resistant cancer cell lines. Some of them exhibited also high therapeutic index and became to be perspective as novel anticancer drugs. Modifi cation of the active substances followed by affi nity chromatography was successful in fi nding the molecular target, which was identifi ed as elongation factor EF1A1. Th e complete mechanism of the drug action inside the cell is not quite clear, but some processes, like complexation with pyruvate kinase M2 were unambiguously identifi ed. According to knowledge of the molecular target we were able to perform molecular modeling and design the new targeted chemical library. Th e problem of these compounds including low solubility, bioavailability and chemical stability was overcome by suitable modifi cation. Th e methods of modifi cation focused on derivatization or encapsulation to various nanoparticles of organic/inorganic matrix will be presented together with physico-chemical as well as biological data. Because the 2P3HQs posses also relevant fl uorescent properties, their potential can lie also in development of novel theranostics.
University of Pretoria, South Africa
Title: Novel in silico-designed anti-cancer compounds: From in vitro exploration to potential clinical considerations
Time : 09:40-10:00
A E Theron qualifi ed as a medical doctor, and after a few years as a trauma and aviation doctor, and then returned to her fi rst interest of molecular medical science. She joined the University of Pretoria in 2009 where she is currently a senior Lecturer in physiology. She is part of a research team involved in developing and investigating novel anti-cancer molecules.
The concept behind these novel in silico-designed anti-cancer compounds encompasses harnessing the well described anti-mitotic eff ects of 2-methoxyestradiol with modifi cations to increase bioavailability, as well as preferential tumour localization via carbonic anhydrase IX binding. Spectrophotometric dose analysis revealed that these novel compounds are cytotoxic at nanomolar concentrations in a number of neoplastic cell types, a property retained in a PgP-overexpressing multi-drug resistant cell line. Microscopy techniques including live imaging of tubulin dynamics confi rmed the induction of apoptosis and autophagy due to alternation of spindle dynamics. Molecular pathways and intracellular responses were assessed via multiple techniques including Western blotting and fl ow cytometry. Chick chorioallantoic membrane assays revealed a signifi cant reduction in primary tumour size and a decreased number of distant metastasis. Ex vivo eff ects on human blood, as well as potential platelet interference were examined both microscopically and via fl ow cytometry. In bridging the gap towards clinical applications, acute mouse toxicity and metabolism studies were performed. Potential eff ects on haematopoietic stem cells were investigated; the results of which indicated that the compounds are not toxic at the IC50 concentrations established for cancer cells. Additionally, aft er drug exposure, stem cells retained their diff erentiating capacity. Potential use of the compounds within a combined treatment regimen was investigated; both with established chemotherepeutic drugs in spectrophotometric matrices, and in radiosensitization studies. Further studies will encompass mouse tumour models, as well as to elucidated whether the conceptual preferential tumour localization is achieved in vivo.
Nova Southeastern University, USA
Time : 10:00-10:20
Dr. Rathinavelu joined NSU in 1992 and is currently holding the Associate Dean for Institutional Planning and Faculty Development position at the College of Pharmacy. He is also serving as the Executive Director of the Rumbaugh Goodwin Institute for Cancer Research (RGI). Dr. Rathinavelu was able to initiate his cancer research in 1993 and from that time onwards his research efforts are focused on discovering new therapeutic targets and novel drugs for cancer treatment. He has published nearly 50 peer-reviewed research articles, serves on the editorial board of scientifi c journals and has conducted peer review of several scientifi c manuscripts for publications. He has also co-authored a text book, written two book chapters and presented more than 75 scientifi c papers in National and International conferences. Among other scientifi c achievements, so far Dr. Rathinavelu has received four patents, one for the discovery of novel assay methods to measure kinases and phosphatases in biological samples. In the spring of 2011 he received 2 patents for the two newly discovered anti-cancer drugs, named F16 and JFD that can starve the cancer and shrink them through anti-angiogenic mechanisms. In the Spring of 2014 one of his anti-angiogenic drugs received the Japanese patent also. Dr. Rathinavelu and his team are planning to enter into collaborative agreements with pharmaceutical companies and take these drugs to early stage clinical trials.
Angiogenesis plays a very important role in controlling the tumor growth and metastatic progression. Evidently, the angiogenic mechanisms are oft en regulated by the microenvironment that surrounds the tumor, thorough the use of hypoxia inducible transcription control process and release of growth factors such as VEGF. Th ough the tumor angiogenesis is regulated by a wide range of intracellular mechanisms, the role for MDM2 in controlling tumor angiogenesis and metastasis has been slowly evolving. Our recent studies have established a strong link between MDM2 and VEGF transcription control mechanisms. Also, interference with the function of the Vascular Endothelial Growth Factor Receptor (VEGFR) has become one of the main strategies to obstruct tumor growth by blocking pro-angiogenic signals. In this respect, several anti-angiogenic blockers are currently available with a wide range of specifi cities and mechanisms. Many of these anti-angiogenic drugs are either monoclonal antibodies with certain specifi city towards neutralizing pro-angiogenic factors or small molecules with an ability to block VEGFR related kinases. However, through molecular modeling approach two new anti-angiogenic drugs were designed at the Rumbugh Goodwin Institute for Cancer Research of NSU to interfere with the binding sites of VEGFR rather than inhibiting the receptor associated kinases. A novel isoindol-amide compound code named F16 and a second compound with a structure that is analogous to purine moiety were identifi ed as new competitive antagonists for VEGF. Both the F16 and JFD have strong anti-angiogenesis potentials since diff erent concentrations (0 to 10 μM) of the experimental drugs can inhibit the tube formation by HUVEC cells on EC-MatrixTM gel. Receptor binding assay with Fluorokine conjugated VEGF in HUVEC cells has also confi rmed a strong competitive binding ability for both F16 and JFD (0.001 to 1.0 μM) in a dose dependent manner. Th e new drugs also show strong anti-cancer eff ects in athymic nude mice that are implanted with GI-101A breast tumor. Interestingly, the combination treatment with Taxol was more eff ective in the xenograft tumor model compared to mono-therapies with F16, JFD or Taxol alone. Results so far clearly suggests that F16 and JFD can specifi cally inhibit VEGF binding to VEGFR2 and reduce phosphorylation that can eventually prevent endothelial cell proliferation and tumor angiogenesis. Furthermore, the results from the in vivo experiments are very conclusive and support the fact that these two small molecules can inhibit tumor growth by blocking VEGFR. At present both in vitro and in vivo experimental results are strong enough to validate F16 and JFD as promising anti-angiogenic agents with signifi cant therapeutic potential.
University of Rome Tor Vergata, Italy
Time : 10:35-10:55
Anna Maria Caccuri graduated with Honors with a degree in Biological Sciences from the University of Rome “Sapienza”. She is Associate Professor of Biochemistry at the Department of Experimental Medicine and Surgery of the University of Rome “Tor Vergata”. She has published 75 papers in reputed peer reviewed journals.
A well-established approach for fi ghting cancer is based on signal-transduction inhibitors directed towards protein kinases involved in tumor development,and oft enused in combination with chemotherapy. However, several chemotherapeutic agents require the activation of the c-Jun N-terminal kinase (JNK) and p38 MAP-kinases to cause tumor cell death; therefore, activation of this pathway may enhance the anti-proliferative and pro-apoptotic eff ects of these drugs. Th e glutathione transferase GSTP1-1, an enzyme present at high levels in many solid tumors and overexpressed in drug-resistant ones, is a natural JNK inhibitor. Th e protein–protein interaction involving GSTP1-1 and JNK is an important mechanism for suppressing the response to apoptotic stimuli in tumors. In this regard, we have obtained biochemical evidence for direct interaction between GSTP1-1 and TNF receptor-associated factor 2 (TRAF2) as well, TRAF2 being an upstream adaptor protein responsible for the activation of JNK and p38. Th e TRAF2-GSTP1-1 complex is constitutively present in diff erent tumor types, but can be disrupted by the strong GSTP1-1 inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX); this results in JNK phospho-activation and tumor cell death. Th erefore, agents directed towards GSTP1-1 and able to activate at diff erent levels the MAPK/JNK signaling cascade may represent an alternative strategy for fi ghting cancer. We have synthesized several NBDHEX derivatives, endowed with higher solubility in water, with excellent tolerability and with antitumor activity against poorly responsive tumors. Th ese compounds are very eff ective in vivo against human melanoma models resistant to vemurafenibor to temozolomide. Th ese fi ndings support the potential use of these novel compounds as part of the new therapies for cancer treatment as single agents or in combination regimens.
University of Tehran, Iran
Title: Possibility of using dopamine receptors specifi c drugs in drug delivery or treatment of lung cancer
Time : 10:55-11:15
Mojhgan Sheikhpour has completed his PhD at the age of 35 years from Tarbiat Modaress University Faculty of Biological Sciences. She teaches and investigates in Tehran University in Iran and has published papers in reputed journals.
Introduction: Th e alterations of fi ve diff erent Dopamine receptor genes expression play multiple roles in various disorders such as cancer. We focused on relationship of dopamine receptor gene expression changes in non small cell lung cancer (NSCLC) disease for design of future therapeutic strategy. Material and methods: We investigated dopamine receptors gene expression changes in peripheral Blood Mononuclear cells of NSCLC patients compared to normal individuals. In addition were done this investigation on samples of lung tissue and Bronchoalveolar Lavage (BAL) of NSCLC patients. Th e extraction of total cellular RNA, cDNA synthesis and Real Time PCR was done for all of samples. Th e statistical comparison between the two groups was carried out using the SPSS soft ware. Th en we investigated apoptosis in a lung carcinoma cell line as an in vitro model of NSCLC using selective agonist of these receptors (BR). Results: Th e results showed a quantitative signifi cant diff erence of D2-like dopamine receptor genes expression in non small cell lung cancer. It has been demonstrated that BR inhibited the proliferation of human lung cancer cells and induced apoptosis in them. Conclusions: Since the receptor pattern has a key role for the choice of the most appropriate treatment schedule for a successful medical therapy, these signifi cant diff erences and profi les could contribute in treatment of non small cell lung cancer by using selective agonist of dopamine receptors as a drug or drug delivery tools.
University of Erciyes, Turkey
Title: Prediction of mechanism of some natural anti-cancerogen agents by using kinetic cell based morphological screening
Time : 11:15-11:35
Mukerrem Betul Yerer-Aycan is a pharmacist, physiologist and an Assoc.Prof. in the fi eld of Pharmacology working in the Erciyes University, Faculty of Pharmacy, Dept. of Pharmacology, Turkey. She is the Chair of the Department since 2007 and the Vice-Dean of the Faculty since 2008. She has studied some parts of her PhD thesis in Spain in 2005 and did her post doc in Switzerland in 2007 and visited Colorado University, Denver, US for a while in 2011 to conduct a common research project. She has 14 papers in SCI and more than 15 national papers and more than 50 presentations in around 30 meetings. She has completed nearly 20 national or international projects from 2005 up to date. She has been awarded nationally or internationally 15 times for her several studies. She is the team leader of 2 MSc and 6 PhD students now and they are recentlyworking on the anticancerogen effects of some natural products. She is in the editorial board of Current Pharmacogenomics and Personalized Medicine and she is an offi cial member of 10 scientifi c societies. She says the biggest due of her career is ‘she is the mother of two sons’.
Drug discovery and development is both time and resource-intensive endeavor which is not always guaranteed to result in safe and effi cacious drugs. Th e eff ective concentration of the compound and importantly the time needed for the compound to perturb the target varies from one compound to another. Taking into account those diff erences and limitations, we used a real time cell analyser that reveals the real time eff ects of the compounds over the impedence alterations on the e-plates. We tested extracts of some natural compounds such as Salvia species, Chrisophtalmum species, Zizyphus species etc., and some natural basic compounds such as gallicasid, ferulic acid, apigenin, luteolin, quercetin, curcumin etc. On several cell lines such as HepG2, A549, SHSY5Y, Colo 205 and Beta TC-6. Th e impedence profi le and the time needed for the coumpound to interact with the cells varied from compound to compund and from cell to cell. We found that some natural compounds with similar biological activity produced similar impedance-based time-dependent cell response profi les (TCRP) as similar to results described over around 2000 chemical compounds before. Due to the kinetic nature of the profi ling approach both short term and long term compound activity can be measured, allowing to guess the probable targets of the compounds on diff erent cell lines. For instance, according to the results of this study the similar compounds showing their eff ects over DNA methylation, PPAR antagonism, cycline dependent kinase inhibition, Ca channel inhibition, tubulin polymerisation, apoptosis or cytotxicity have similar TCRPs with the real time cell analyser. In our study, we observed similar results with the natural compound extracts or basic natural compounds. Th ese fi ndings indicate that using impedance-based monitoring and profi ling of cellular response upon exposure to biologically active compounds can provide incisive and quantitative information to novel mechanisms for these natural compounds.
Cairo University, Egypt
Title: Effect of mesenchymal stem cells and a curcumin derivative on notch1 signaling in hepatocellular carcinoma in rats
Time : 11:35-11:55
Walaa Ibrahim Ali Ahmed has completed her PhD at the age of 31 years from Faculty of Medicine, Cairo University. She is a Lecturer of Medical Biochemistry and Molecular Biology at Faculty of Medicine, Cairo University and is one of the active members of the unit of biochemistry and molecular biology (UBMB) at Kasr Alainy School of Medicine for 6 years. She has published one paper in reputed journal.
The Notch1 receptor and signaling pathway is upregulated in HCC. Th e present study was conducted to evaluate the eff ect of mesenchymal stem cells (MSCs) and a novel curcumin derivative (NCD) on hepatocellular carcinoma (HCC) in hepatoma induced rats, and to investigate their eff ect on Notch1 signaling pathway target genes. One hundred rats were divided equally into: control group, control group received MSCs, control group received a NCD, HCC group, HCC group received MSCs only, HCC group received a NCD only, HCC group received MSCs and a NCD simultaneously, HCC group received MSCs followed by a NCD 2 weeks later, HCC group received MSCs pretreated with a NCD and HCC group received MSCs conditioned medium (CM). Histopathological examination, gene expression of Notch1 signaling target genes by RT-PCR in rat liver tissue were assessed and serum levels of alpha fetoprotein, ALT and albumin were assesed in all groups. Administration of MSCs or a NCD aft er induction of HCC improved the histopathological picture while administration of MSCs and a NCD or MSCs pretreated with a NCD showed restoration of liver parenchyma. Notch1 and its target genes were downregulated in all treated groups. Liver function was ameliorated in all treated groups. Th ese data suggest that modulation of Notch1 signaling pathway by MSCs and/or NCD may be considered as a therapeutic target in HCC.
Chiba University, Japan
Time : 11:55-12:15
Hiroshi Kobayashi has completed his PhD (1974) in Biochemistry from University of Tokyo in Japan. After his Postdoctoral training at Colorado University Medical Center in USA, he started to study adaptation strategies of microorganisms to acidic environments at Chiba University in 1978. His recent research is focused on mammalian cell functions under acidic conditions from 1996 at Graduate School of Pharmaceutical Sciences, Chiba University. He retired in March 2012 and continues his research as a Professor Emeritus at Chiba University. He has published more than 20 papers in reputed journals during the recent 10 years.
Although blood and tissues are usually maintained at pH around 7.4 in mammals, the extracellular pH drops below 6.5 in solid cancer nests. Such acidic environments may decrease intracellular pH and disrupt cellular functions mediated by a large number of enzymes with pH sensitive catalytic activity. Target molecules of anti-cancer drugs are largely enzymes whose activity is dependent on pH, suggesting that the effi cacy of anti-cancer drugs varies as pH changes. We have measured the inhibitory eff ect of over 270 well-known compounds on cancer cell proliferation in media of pH 7.5 and 6.7, and fi ve compounds, lovastatin, cantharidin, manumycin A, doxorubicin, and ionomycin, showed high inhibition at pH 6.7, but their inhibitory eff ects were low at pH 7.5. We further examined the inhibitory mechanism of statins and found that the inhibition was caused by the decrease in protein geranylgeranylation. Clinical investigations have revealed the therapeutic eff ect of statins on cancer patients. It can be argued that the anti-cancer drugs with high effi cacy under acidic conditions have low side eff ects on cells in normal tissues, especially immune cells in blood, because normal tissues and blood are generally slightly alkaline. In fact, statins are now prescribed for the treatment of hyperlipidemia with low side eff ects. Th ese results suggested that the screening of anti-cancer compounds in acidic medium would be useful for development of new anti-cancer chemotherapeutics.
Escuela Superior de Medicina- IPN, Mexico
Time : 12:15 -12:35
José G Trujillo-Ferrara, a pioneer in Mexico in the fi eld of Medicinal Chemistry has focused on the rational drug design based on the molecular mechanisms of pathology. Experiments are done in vitro, in vivo and in silico to predict which compound will have the greatest effect in clinical use. He has authored more than 100 publications and has more than 600 citations. He is a member of the National System of Researchers II and a Board Editor of the Journal of Enzyme Inhibition and Medicinal Chemistry. He has been the advisor for 62 students to obtain a scholar degree.
Today the most common target of chemotherapy ligands that aim to avoid cell proliferation is a direct attack on DNA. Th is focus has a major drawback, which is that the DNA of cancer and healthy cells is the same, meaning that the therapy is not selective and it’s necessary to use several diff erent compounds. Th e epigenetic is aimed at the DNA environment and not a direct attack on DNA. Th is was the focus of the last contribution, which aim was to synthesize pro-apoptotic molecules that are α,β-unsaturated aryl amides, these compounds are highly selective for thiol-containing compounds, which are abundant in cancer cells. By targeting the DNA environment, cancer cells can be made more sensitive to attack by histone deacetlylaseinhibitors and ornithine decarboxylase-inhibitors. Th e aim of this contribution was to design a dual targeting molecule that inhibits both ornithine decarboxylase (ODC) and histone deacetylase (HDAC). Actually, we found two molecules that serve this purpose; these molecules are ω-chloroacetyl ornithine and ω-chloroacetyl lysine. Th ese molecules were tested in silico and in vitro. In both molecules docking clearly showed that the carboxylic moiety is the binding site of ODC while the chloroacetyl moiety is the binding site of HDAC. Th e in vitro studies showed an inhibition constant of 1.5 μM for both ODC and HDAC. Th e eff ect of both molecules was determined on three diff erent cell lines: Vero, HeLa, and Hep G2 cells. Th e results clearly show time-dependent and concentration-dependent inhibition of proliferation of cancer cells without any eff ect on healthy cells.
Universidade Nova de Lisboa, Portugal
Time : 12:35-12:55
João Paulo Borges has a PhD in Macromolecular Materials. His research activity is devoted to the development of new materials for Tissue Engineering and magnetic nanoparticles for cancer theranostics. From 2008 to 2014 he was Vice-director of the Materials Research Centre/Institute of Nanostructures, Nanomodeling and Nanofabrication - CENIMAT/I3N. He is coordinator of the MSc in Materials Engineering and member of the executive and scientifi c boards of the Materials Science Department of Faculty of Science and Technology, Lisbon. He is Editor of the journals “Journal of Composites and Biodegradable Polymers”, “International Journal of Chemoinformatics and Chemical Engineering” and Annals of Materials Science & Engineering.
The main subject of this lecture is the synthesis and characterization of multifunctional nanoparticles for cancer theranostic. Th eranostic nanomedicine for cancer is currently the most promising approach to kill cancer. In this context we synthetized a multifunctional nano-platform composed of an iron oxide core which gives the dual function: Treatment through hyperthermia and treatment monitoring through magnetic resonance image. Further, the core is coated with a biocompatible and biodegradable polymer, giving not only protection to the core, but also to serve as a platform for drug delivery or targeting. Th e attendees of this lecture will be familiarized with infl uence that surfactants and the polymeric coating have on the physicochemical and magnetic properties, stability and heating ability of iron oxide colloids. In addition, the theranostic properties of these multifunctional nanoparticles will be explained and demonstrated.
Our investigations establish linear correlations between the ionization potential of exogenous phenol (P) and fl avone (F) derivatives and their biological eff ects on induction of a powerful cancer-protective enzyme NAD(P)H:quinone reductase (NQO1) via the Nrf2-Keap1 pathway. Th ey also show that the NQO1 activation involves (i) oxidation of the P and F inducers to oxidant species which are their quinone derivatives (Q) and (ii) oxidation by these quinones Q of two highly reactive thiol groups of a protein Keap1 activating transcription factor Nrf2. Th e linear correlations observed for benefi cial cancerprotective pathways triggered by electrophiles Q in vitro explain the linear correlations which we observe in vivo (rodents) for the inhibition of chemically-induced carcinogenesis by P and F derivatives. Our in silico evaluation of biological activity of P and F derivatives should orient the rational design of new congeners with greater potency for cancer chemoprotection and might reduce the expensive use of in vivo and in vitro bioassays.
Texas State University, USA
Title: Discovery of a novel tubulin-targeting scaffold derived from the rigidin family of marine alkaloids
Time : 14:05-14:25
Alexander Kornienko has recently accepted a position of an Associate Professor of Chemistry at Texas State University after having held an academic position at New Mexico Tech since 2001. His teaching and research interests encompass the discovery of new reactions and methods in synthetic organic chemistry, natural product isolation and derivatization, and cancer drug development. Professor Kornienko has published 70 research papers and trained numerous students in research disciplines on the chemistry-biology interface. His current projects focus on applying synthetic chemistry toward advancing a number of anticancer natural products, specifi cally active against apoptosis-resistant tumors, to human clinical trials.
We developed synthetic chemistry to access the marine alkaloid rigidins and over forty synthetic analogues based on the 7-deazaxanthine, 7-deazaadenine, 7-deazapurine and 7-deazahypoxanthine skeletons. Analogues based on the 7-deazahypoxanthine skeleton exhibit ednanomolar potencies against cell lines representing cancers with dismal prognoses, tumor metastases and multidrug resistant cells. Studies aimed at elucidating the mode(s) of action of the 7-deazahypoxanthines in cancer cells revealed that they inhibited in vitro tubulin polymerizatio n and disorganized microtubules in live HeLa cells. Experiments evaluating the eff ects of the 7-deazahypoxanthines on the binding of [3H]colchicine to tubulin identifi ed the colchicine site on tubulin as the most likely target for these compounds in cancer cells. Because many microtubule-targeting compounds are successfully used to fi ght cancer in the clinic, we believe the new chemical class of antitubulin agents represented by the 7-deazahypoxanthine rigidin analogues have signifi cant potential as new anticancer agents.
Universiti Sains Malaysia, Malaysia
Title: In situ detection of Polyalthia longifolia leaf extract in developing natural anti-cancer therapeutic agent: Optical and electron microscopy evidence
Time : 14:25-14:45
Soundararajan Vijayarathna is a second year Doctoral student in Molecular Medicine at Universiti Sains Malaysia (USM). She has published more than 12 papers, 5 proceedings and contributed to a book chapter. Currently, her fi eld of research addresses the relationship of microRNAs with cancer biology and the role of natural products as anti-cancer agents. She won the most “Excellent Paper” award for her oral presentation at 2012 3rd International conference on Biotechnology and Food Science in Bangkok, Thailand and been nominated for Best Thesis Award by the Institute for Research in Molecular Medicine in USM for her MSc thesis.
Optical and electron microscopes are extensively employed scientifi c techniques, which gauge cytological changes as incur in cell cytotoxicity. Th e microscopic images relinquish topographical, morphological and compositional evidences that infer cell mechanism in response to anticancer agent. On that ground, this study engaged numbers of microscopy methods to detect in situ anticancer activity of Polyalthia longifolia against cervical cancer cell line, HeLa. Th e P. longifolia being the most important indigenous medicinal plants, are found throughout Malaysia and generally use by traditional healers to treat various diseases. Th e MTT assay results disclosed the lowest IC50 value of 14.181 μg/ml as P. longifolia leaf extract debilitate HeLa cells. Th e eff ect of this plant extract on HeLa cells were observed at 0, 6, 12, 24 and 36 hours using Light Microscope (LM), Scanning Electron Microscope (SEM), Transmission Electron Microscope (TEM) and HoloMonitor (HM). Th e cytological observations underlined cell shrinkage, nuclear and chromatin condensation, multinucleation, membrane blebbing, punctures, cytoplasmic extrusions and formation of apoptotic bodies, which are correlating within LM, SEM, TEM and HM images. Further biochemical tests were performed to verify this apoptosis resemblance. P. longifolia is deduced to eff ectuate distinctive morphological features of cell death in conformity to apoptosis. Th e fi ndings corroborate P. longifolia as a potential natural therapeutic agent in combating cervical cancer, which ranks the world’s second largest cause of female cancer mortality.
Fudan University, China
Title: GPCR-Like signaling mediated by smoothened contributes to acquired chemoresistance through activating Gli
Time : 14:45-15:05
Wenfu Tan is a faculty in Department of Pharmacology, School of Pharmacy, Fudan University.
Background: Smoothened (Smo), which possesses a structural similarity with classic G-protein coupled receptors (GPCR), is the most important molecular target in Hedgehog (Hh) signaling system for developing anticancer drugs; however, whether Smo may transmit GPCR-like signaling to activate the canonical transcriptional factor Gli of Hh signaling system and consequently to be involved in the Gli-dependent biological events remains controversial. Results: In this study, using the acquired chemoresistant cancer cell lines and their respective parental cells, we found that Smo may activate Gli through Gai, Gb-JNK signaling axis, thereby promoting the Gli-dependent acquired chemoresistance. Th ese observations were further complementarily strengthened by data obtained from chemosensitive cancer cells wit h artifi cially elevated Hh pathway activity. Conclusions: Hence, our data demonstrate that GPCR-like signaling mediated by Smo contributes to the acquired chemoresistance through activating the canonical Hh transcriptional factor Gli; therefore improving our knowledge of the nature of the signal transduction of Smo and the molecular mechanisms responsible for the acquired chemoresistance maintained by Hh pathway. Moreover, our data that JNK aft er activated by Smo-Gb signaling axis may stimulate the Gliactivity and consequently promotes acquired chemoresistance expose a promising and potential target for developing anti-cancer drugs aimed at Hh pathway and for combating the acquired resistance raised by using of anti-cancer drugs targeting Smo.
Universiti Sains Malaysia, Malaysia
Title: Euphorbia hirta induces S and G2/M cell cycle arrest and apoptosis in MCF-7 breast cancer cells
Time : 15:05-15:25
Sreenivasan Sasidharan has completed his PhD from Universiti Sains Malaysia in 2007. He is the Senior Lecturer in Institute for Research in Molecular Medicine of Universiti Sains Malaysia, a public University in Malaysia. He has published more than 100 papers in reputed journals and has been serving as an Editorial Board Member and Reviewer of international journals.
Euphorbia hirta species has been used as a folk remedy in Southeast Asia for the treatment of various ailments. Th e purpose of this study was to evaluate the inhibitory eff ect of E. hirta extract on human breast cancer MCF-7 cells and investigate the possible mechanism of E. hirta. Various cytotoxicity assays, microscopes method and fl ow cytometry study was conducted to study the anticancer activity of E. hirta. Th e MTT assay showed that E. hirta inhibited MCF-7 cell viability in a dose and time-dependent manner. Microscopic studies showed that E. hirta treated cells exhibited marked morphological features characteristic of apoptosis. E. hirta extract also had an ignorable infl uence on the LDH leakage and generating intracellular ROS. Th e Annexin V/Propidium Iodide fl ow cytometry study confi rmed that E. hirta extract induced apoptosis in MCF-7 cells. E. hirta extract treatment also resulted in DNA fragmentation in MCF-7 cells. Moreover, E. hirta treatment resulted in the accumulation of cells at the S and G2/M phases as well as apoptosis. Th e caspase activity study revealed that E. hirta extract induced apoptosis through the caspase-3 independent pathway by the activation of caspase-2, 6, 8 and 9. To identify the cytotoxic fraction, E. hirta extract was subjected to bioassay-guided fractionation. E. hirta hexane fraction, namely EH Hex 4 demonstrated highest activity among all the fractions tested. Th is study revealed that E. hirta induced apoptotic cell death and suggests that E. hirta could be used as an apoptosis-inducing anti-cancer agent for breast cancer treatment with further detailed studies.
Indian Institute of Technology, India
Title: Synthesis and biological evaluation of some exquisite molecules towards mutagenesis and anticancer activities
Time : 15:40-16:00
Jayanta K Ray has completed his PhD at the age of 26 years from Calcutta University and Postdoctoral studies from University of Chicago and Drexel University, Philadelphia. He served as Chairman, Department of Chemistry, Indian Institute of Technology, Kharagpur, a premier Institute. He has published more than 125 papers in reputed journals.
Chloro and bromo vinyl aldehydes have been used as starting material for the synthesis of diff erent small ring heterocyclic systems with exo-cyclic functionalities. Highly regioselective direct alkylation/arylation methods have also been developed to functionalize the heterocyclic compounds. Core and fi ne tuning of structural motifs generated interesting host molecules to embrace neutral guest in the cavity by weak electrostatic interactions. Carbocyclic frame works have also been achieved from bromo vinyl aldehydes by Pd catalysed Ullmann cross coupling reactions have been utilized to synthesise bio-active natural products and designed molecules. Annulated bromovinyl aldehydes were converted to 5-7 member cyclic ketones by Heck-type reaction. Shortest synthesis of Cuparene from bromoaldehydes has also been achieved. Th e uses of the methodology developed have been explored for the synthesis of bioactive natural and designed molecules including some compounds having mutagenic activities viz terminal thiophene diol epoxides fi rst example of this class of compounds and we have also observed removing the dihydrodiol moiety with pyrananone fused polycycles totally diff erent activities like anticancer properties. Th us Qualitative Structure Activity (QSAR) relationship has been established, and it has been observed that in tetracyclic frame works of poly carbo and hetero cyclic compounds the introduction of diol epoxide moiety in the terminal ring induces mutagenic activities whereas replacement of Diolepoxide moiety by pyaranone produces anti caracinogenic eff ects. Th e method is useful to generate functionality in the polycyclic frame works. Th e stereo controlled chemo and region selectivity have recently been developed. Mechanistic details will also be presented.
Escuela Superior de Medicinadel IPN, Mexico
Title: Aryl maleimides as apoptosis inducers on L5178-Y murine leukemia cells (in silico, in vitro and ex vivo study)
Time : 16:00-16:20
Erik Andrade-Jorge is a Doctorate student in the Department of Biochemistry at Politecnico Nacional. He is a chemist pharmaceutical biologist and has a Master degree in Pharmacology Science and is currently in the second semester of the Doctorate in medicinal investigation. Currently, he has three different research lines one of these is cancer cell proliferation, another one is in Parkinson’s disease and the third one is in obesity. He has focused on the rational drug design based on the molecular mechanisms of different pathologies.
Mitochondria is one of the most important organelles and alterations in the function of their membranes, like those caused by high levels of free radical, are pivotal in the initiation of cell death by apoptosis. Th iol oxidation or cross-linking reactions are associated with a higher probability of an open transmembrane pore leading to the release of pro-apoptotic molecules and cell death via apoptosis. Th erefore, the aim of the present study was to design a series of aryl maleimides that are α,β-unsaturated compounds to test their selectivity for thiols in diff erent experiments. NMR spectra confi rmed the structures of eight aryl maleimides synthesized (1a-1h). Two aryl maleimides (1f and 1h) were tested with an in vitro and ex vivo model to evaluate their reactivity with thiols and their activity in L5178-Y murine leukemia cells, the in vitro reactions clearly showed a chemoselective Michael type 1,4-addition reaction between thiols and the aryl maleimides as predicted in theoretical calculations. In cell cultures, the compounds induced a decreasing cellular viability and an apoptotic eff ect of up to 59.8% at 48 h. Th is was confi rmed by cytofl uorometry, DNA fragmentation and morphological changes in the cells. Th e ex vivo experiment showed an important reduction of thiol levels in cells treated with 1h. Results strongly suggest that aryl maleimides can make cancer cells more susceptible to die by apoptosis due to decreasing the levels of glutathione; therefore, aryl maleimides could be used to make cancer cells more sensitive to a less aggressive treatment than the currently used chemotherapy.
Title: Signifi cant cancer inhibitory effects of vitamin D3 400 I.U. on various cancer activities non-invasively detected by reduction of integrin α5β1, oncogene C-fosAb2, 8-OH-dG, & TXB2, and undesirable cancerpromoting effects & invisible harmful biochemical changes of the heart found on the face & ECGs of commonly used vitamin D3 doses of 2000 I.U. or higher
Time : 16:20-16:40
Yoshiaki Omura received both Oncology Residency Training and a Doctor of Science Degree through research on Pharmaco-Electro Physiology of Single Cardiac Cells in vivo and in vitro from Columbia University. He has published over 250 articles and 7 books. He is Executive Editor of Integrative Oncology & Editorial Board Member of Journal of Clinical Trials in Cardiology, etc. Using his new diagnostic method, which received U.S. patent, he can non-invasively and rapidly measure many neurotransmitters, other chemicals, asbestos, viruses, and bacteria. He developed non-invasive quick diagnostic methods of malignancies, as well as a method of evaluating the effects of any treatment.
Recently many physicians are giving 2000 I.U. of Vitamin D3 for cancer patients, which increases cancer activities signifi cantly (3~5 times) in our study. Some are given even 5000 I.U. However, when 400 I.U. of Vitamin D3 is given to most adult patients, cancer activities will be signifi cantly reduced anywhere between 1/5~1/100 with decrease in Integrin α5β1, Oncogene C-fosAb2, 8-OH-dG and TXB2. We found Vitamin D3 400 I.U. oft en eliminates angina pain rapidly. When 2000 I.U. or higher doses of Vitamin D3 are used, standard ECG soft en do not show signifi cant visible changes,even when the patient is developing discomfort or mild pain in the heart. However, we found there is a signifi cant undesirable invisible biochemical changes including increase in Cardiac Troponin I, TXB2, and Calcium can be found at the rising part of the T-Wave known as “Vulnerable Period for Ventricular Fibrillation (V.P.F.V.F.).”While, physicians only examine the shape and amplitude of the electrical potential, but our study indicated that each part of the ECG contains invisible biochemical information corresponding to specifi c parts of the heart and this information can be detected using Electromagnetic Field(EMF) Resonance Phenomenon between 2 identical molecules, since recorded ECGs contain EMF information of many invisible biochemical substances in the heart on the recorded ECGs & heart representation areas of the face. Non-invasively measured invisible molecular information in diff erent parts of the electrocardiograms clearly indicate 400 I.U. of Vitamin D3 can reduce abnormally high Cardiac Troponin I, TXB2 and Calcium. When 2000 I.U. or higher amount of Vitamin D3 is used, it can cause life threatening invisible biochemical changes, particularly in heart patients.
Dr. H. S. Gour Central University, India
Time : 16:40-17:00
Ankit Jain with a breakthrough out of his diligence, scored 99.34 percentile in GATE-2008, (in BPharm III year). He got valuable scholarships like JRF-UGC and SASS (New Delhi) in his study period. He is also a recipient of Young Jaina Award-2012. He owned number of best papers in national seminars and has more than 15 international publications including book chapters in reputed journals to his credit. Currently, he is pursuing PhD (CSIR-SRF) under kind supervision of Prof. Sanjay K. Jain (Professor in Pharmaceutics), Dept. of Pharm. Sciences, Dr. H.S. Gour Central University, Sagar (M.P.), India. His research areas of interest include novel cancer targeting strategies, liposomal research and fabrication of drug nanocarriers.
Ovarian cancer is one of the most fatal gynecologic cancers. In this debut study, dual approach using synergistically active combination of paclitaxel-topotecan (Pac-Top; 20:1, w/w) is investigated with utilization of characteristic features of tumor micro-environment and additionally over expressed folate receptors (FR-ɑ) to achieve targeting to tumor site. Various liposomes namely: Liposomes, PEGylated liposomes and FR-targeted PEGylated liposomes with lipid compositions viz. DPPC: DMPG (85.5:9.5), DPPC: DMPG: mPEG2000-DSPE (85.5:9.5:5) and DPPC: DMPG: mPEG2000-DSPE: DSPE-PEG-folate (85.5:9.5:4.5:0.5), respectively were developed using thin fi lm casting method. Th ese were nanometeric in size around 200 nm. In vitro drug release study showed initial burst release followed by sustained release for more than 72 hrs at physiological milieu (37±0.5ºC, pH 7.4) while burst release (i.e. more than 90%) within 5 min at simulated tumor milieu (41±1ºC, pH 4). SRB cytotoxicity assay in OVCAR-3 cell line revealed Pac-Top free (20:1, w/w) to be more toxic (GI50= 6.5 μg/ml) than positive control (Adriamycin, GI50= 9.1 μg/ml) and FR-targeted PEGylated liposomes GI50 (14.7 μg/ml). Moreover, fl orescence microscopy showed the highest cell uptake of FR-targeted PEGylated liposomes so called “Smart Liposomes” which has not only mediated eff ective targeting to FR-ɑ but also triggered release of drugs upon hyperthermia.
University Center of Araraquara (Uniara)
Title: Aerobic but not resistance training is effective to counteract colonic preneoplastic lesions in mice
Time : 17:00-17:20
Fernando Tadeu Trevisan Frajacomo have a degree in Physical Therapy from the School of Ribeirão Preto Medical -FMRP / USP (2007), Masters and PhD in Medical Sciences from the same institution. Specializing in resistance training applied to the health and performance from the University Center of Araraquara (Uniara) in 2010. He have experience in resistive and aerobic exercise area in clinical and experimental studies on the prevention and treatment of cancer, as well as the focus of eccentric training in older adults and athletes.
University of Delhi, India
Time : 17:20-17:40
Neha Jaiswal is currently persuing PhD from University of Delhi South Campus. Her research interest focuses on the elucidation of mechanisms underlying HPV mediated oncogenesis. She has authored four peer reviewed publications. She has also attended several national and international conferences and has several poster awards to her credit. Her work was also selected for oral presentation and received an award of excellence at 3rd International Conference of Carcinogenesis Foundation in 2012.
Cervical cancer is the leading cause of death in women worldwide and is primarily associated with persistent infection of high-risk human papillomavirus (HPV). Th e oncogenic transcription factor, Forkhead box M1b (FoxM1b) is often overexpressed in many human tumors including cervical cancer, signifying its participation in tumorigenesis. Its proven role in carcinogenesis and its prospect as a promising therapeutic in cancer makes it a molecule of considerable clinical interest. Interestingly, post-translational modifi cations of FoxM1 have been shown to modulate its activity in cell cycle control, genomic stability and tumorigenesis. A thorough understanding of FoxM1 will be extremely useful in the innovation of more rationalized strategies for treating and preventing cancer. Here, we report that FoxM1b interacts with SUMOylating enzymes Ubc9 and PIAS1 and subjected to SUMOylation. We also demonstrate that SUMOylation contributes to destabilization and nucleocytoplasmic shuttling of FoxM1b protein. More importantly, our work provides the fi rst evidence regarding a role of E7 oncoprotein in HPV mediated upregulation of FoxM1b. Th e elevated expression of FoxM1 was determined to be posttranscriptional and was attributed to decreased SUMOylation of FoxM1b in the E7-expressing cells. Th us, our study provides valuable insights into SUMOylation dynamics of FoxM1bas well as identifi es the biochemical mechanism that high risk HPV exploits to induce malignant transformation. Altogether, the investigation enriches our understanding of the mechanisms of HPV oncogenesis in development of cervical carcinoma which may facilitate in the discovery of new anticancer strategies.
University of Karachi, Pakistan
Title: Novel TP53 three dimensional (3D) hot spot mutationsat codon 36, 72 and 240 in oral squamous cell carcinoma: A promising diagnostic tool for future immunotherapies
Time : 17:40-18:00
Abid Azhar is a faculty in University of Karachi, Pakistan.
Oral squamous cell carcinoma (OSCC) is the leading cause of death in the developing countries like Pakistan. Th is problem aggravates because of the excessive use of available chewing products. In spite of widespread information on their use and purported legislations against their use,the Pakistani markets are classical examples of selling chewable carcinogenic mutagens. Reported studies indicated that these products are rich in reactive oxygen species (ROS) and polyphenols. TP53 gene is involved in the suppression of tumor. It has been reported that somatic mutations caused by TP53 gene are the foundation of the cancer.Th is study aims to fi nd the loss of TP53 functions due to mutation/polymorphism caused by genomic alteration and interaction with tobacco and its related ingredients. Total 260 tissue and blood specimens were collected from OSCC patients and compared with age and sex matched controls. Mutations in exons 2-11 of TP53 were examined by PCR-SSCP. Samples showing mobility shift were directly sequenced. Two mutations were found in exon 4 at nucleotide position 108 and 215 and one in exon 7 at nucleotide position 719of the coding sequence in patient’s tumor samples. Th ese result in substitutionof proline with arginine at codon72 and serine with threonine at codon 240 of p53 protein.Th ese polymorphic changes, found in tumor samples of OSCC, could be involved in loss of heterozygocity and apoptotic activity in the binding domain of TP53. Th e model of the mutated TP53 gene elaborated a nonfunctional unfolded p53 protein, suggesting an important role of these mutations in p53 protein inactivation and malfunction. Th is nonfunctional 3D model also indicates that exogenous tobacco related carcinogens may act as DNA-damaging agents aff ecting the structure of DNA.Th e interpretationscould be helpful in establishing the pathways responsible for tumor formation in OSCC patients.