14^th World Congress on Pharmacology and Toxicology September 11-12, 2019 Singapore

Biography:

Gautam Sethi has completed his Postdoctoral training at University of Texas, Anderson Cancer Center, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore as an Assistant Professor and Associate Professor. He currently serves as an Academic Editor for PLOS, Editorial Board Member of Scientific Reports, Pharmacological Research, BMC Cancer, Frontiers in Pharmacology, Frontiers in Oncology, Journal of Natural Products in Cancer Prevention and Therapy and ad-hoc Reviewer for several other prestigious international journals.

Abstract:

Signal Transducers and Activators of Transcription (STATs) comprise an important class of transcription factors that have been implicated in a wide variety of essential cellular functions related to proliferation, survival, and angiogenesis. Among various STAT members, STAT3 is frequently overexpressed in tumor cells as well as tissue samples and regulates the expression of numerous oncogenic genes controlling the growth and metastasis of tumor cells. I will briefly discuss the importance of STAT3 as a potential target for prostate cancer therapy and also provide novel insights into various classes of existing pharmacological inhibitors of this transcription factor that can be potentially developed as anti-cancer drugs.

Biography:

Abdelkader E Ashour has completed his PhD(Drug Discovery) from the University of Nebraska Medical Center at Omaha, USA and Postdoctoral studies at UNMC. He has received prestigious Harris Award for Excellence and Outstanding Work in Cancer Research. He has published 60 research papers in reputed journals.

Abstract:

CARP-1/CCAR1 is a perinuclear phosphoprotein which functions as a co-activator of the cell cycle regulatory anaphase promoting complex/cyclosome (APC/C) E3 ligase. CARP-1 functional mimetics (CFMs) are a class of small molecule compounds that inhibit CARP-1 binding with APC/C subunit APC-2. CFM-4, a lead compound, was found to be a potent antitumor agent that suppresses growth and metastasis of various tumor cells including medulloblastoma, neuroblastoma, malignant pleural mesothelioma, lung and breast cancers, in part by stimulating apoptosis. Recently, we examined the possible inhibitory effects CFM-4 against proliferation and metastasis of Colorectal Cancer (CRC). CRC constitutes one of the most aggressive malignancies worldwide. Existing anti-tumor treatments clinically applied for CRC include surgery, radiotherapy and chemotherapy. The high incidence of metastasis and toxic side effects of therapies, as well as low response rates of CRC to chemotherapy indicate that existing treatment methodologies remain unsatisfactory. Thus, it is crucial to develop more efficient and less noxious treatment modalities for this disease. In this recent study, we investigated the growth inhibitory potential of the CFM-4 on CRC and found that CFM-4 inhibits colon cancer cell proliferation in a dose and time dependent manner. Notably, CFM-4 was much more potent than the classical anti-colorectal cancer 5-fluorouracil. The growth inhibitory effects of CFM-4 against CRC cells were mediated at least in part by stimulating apoptosis, as indicated in our Annexin V/Propidium iodide (PI) apoptosis assay results. To molecularly assess the effects of CFM-4 as antitumor agent against human colorectal HT-29 cells, mRNA expression analysis by qPCR was also utilized. Results revealed upregulation of expression of caspase-8 and caspase-9, as well as p53 and its downstream targets, PUMA, Noxa, Smac which play a crucial part in promoting mitochondrial apoptotic pathway. Pro-apoptotic molecules known to initiate the extrinsic apoptotic pathway including TRAIL death receptors (DR4 and DR5) were also upregulated. These results suggest that CFM-4 induces both intrinsic and extrinsic pathways of apoptosis. The influence of CFM-4 on mRNA expression of the NF-kB signaling inhibitor A20-binding inhibitor protein (ABIN1) was also assessed and revealed upregulated. Although CFM-4 did not significantly affect the expression of the PI3K downstream effector AKT, it remarkably upregulated the PI3K negative regulator PTEN. Moreover, we examined CFM-4 effects on colon cancer cell cycle and observed that CFM-4 has significantly induced G2/M phase arrest and dose-dependent increase in sub-G1 peak, indicative of apoptosis, of the cell cycle of the colon cancer HT-29 cells, further substantiating our Annexin V/PI apoptosis results. Furthermore, western blot analysis results revealed that CFM-4 enhanced expression of CARP-1, as well as the initiator caspase, caspase-8, and the executioner caspase, caspase-3. On the other hand, metastatic properties of the HT-29 CRC cells were reduced by CFM-4 through blocking their capabilities to form colonies, migrate and invade through the matrix-coated membranes. These results revealed that the potent antitumor and anti-metastatic properties of CFM-4 against CRC are due to collective pro-apoptotic, anti-proliferative and anti-invasive activities. Together the data warrants further investigations of CFM-4 as potential anti-tumor agent for CRC malignancy and metastasis.

Biography:

Lisa BG Tee has a broad research interest in drug metabolism and paracetamol toxicity, liver cancer, diabetes and nerve regeneration building on her expertise in tissue & cell culture, confocal imaging and pharmacological research. She was awarded in her capacity as chief investigator grants from the NMHRC, Cancer Foundation and Raine Foundation. Whilst she have a strong interest in research, her passion for teaching in the discipline of Medical and Health Sciences has led her towards teaching in Pharmacology, Human Biology, Biochemistry, Immunology and Microbiology. Lisa has recently been awarded the Australian National Excellence and Innovation in Teaching Award as well as a recipient of the National Teaching Fellowship.

Abstract:

Background: It is well known that paracetamol can induce hepatotoxicity when an excessive amount is consumed. Quantities above the recommended therapeutic dose cause the production of the toxic metabolite, NAPQI, which causes the generation of radicals resulting in the depletion of glutathione stores. Subsequently, the hepatocyte is vulnerable to injury. However the mechanism of destruction is still not fully understood and as a result, the field of drug-induced liver damage requires further study to further understand the impact paracetamol has on a liver cell. With new technology and live cell imaging via confocal microscopy, this study was able to document the morphological changes in isolated hepatocytes exposed to paracetamol. Methodology and Results: This study investigates the effect of dithiotreitol and N-acetylcysteine in reversing paracetamol toxicity. Cultured AML12 mouse hepatocytes were pre-incubated with 0 or 2.5mM paracetamol. At 4.5 h, toxicity was evident in paracetamol-treated but not control cells. Hepatocytes exposed to paracetamol exhibited mitochondrial depolarisation and decreased cell viability. Confocal microscopy studies with bright-field microscopy and MitoTracker dye indicated that changes in cell morphology and mitochondria occurred as a result of the paracetamol-induced  toxicity. Conclusion and Significance: This data is consistent with the hypothesis that at excessive concentration, paracetamol is metabolised into N-acetyl-p-benzoquinone imine (NAPQI) within 90 minutes. Addition of 1.5mM dithiothreitol (DTT), a reducing agent, or 1.25mM N-acetylcysteine (NAC), a glutathione precursor, after paracetamol preincubation increased cell viability and reduced mitochondrial depolarisation. Live imaging indicated that cell injury was lower after the addition of DTT and NAC. DTT and NAC showed no toxicity to hepatocytes when added individually. These data support the hypothesis that DTT reverses oxidative stress induced by NAPQI, probably by reducing oxidised disulphide groups found in essential mitochondrial proteins into thiols.

Biography:

Petra Czarniak has completed her PhD at Curtin University, Western Australia. She is currently working as a Senior Lecturer in the School of Pharmacy and Biomedical Sciences. Her current research interests include the quality use of medicines, medication misuse, extended clinical services in pharmacy, stability of off-label and unlicensed drugs and antimicrobial stewardship.

Abstract:

Introduction & Objective: Data on the off-label and unlicensed medicines use in paediatric patients in the hospital setting in Indonesia is limited. The objectives of the study were to evaluate the prevalence of off-label and unlicensed prescribing at a paediatric medical ward at Abepura Hospital, Indonesia and to identify which drugs were commonly prescribed off-label or unlicensed.

Method: A retrospective cross-sectional study was conducted to collect data on 200 randomly selected patients in 2014, including data on all drugs prescribed. Drugs were categorized as licensed, off-label or unlicensed, according to their approved Indonesian registration Product Information. Unlicensed drugs/formulations were those not registered in Indonesia.

Results: There were 124 (62.0%) males and 76 (38.0%) females. Of the 200 patients (aged 1 month to 13.2 years), 1961 medicines were administered of which 1807 (92.1%) were licensed and 154 (7.9%) were unlicensed. Of the licensed drugs, 1403 (71.5%) were prescribed off-label. Many drugs (1066; 54.4%) were administered parenteral and every patient was prescribed at least one off-label drug. The most common reason for off-label prescribing was indication (810; 34.6%). The most frequent drug prescribed off-label was ranitidine. Darplex® (Dihydroartemisinin and Piperaquine), which was manufactured but not registered in Indonesia, was the most common drug prescribed unlicensed.

Conclusion: This study revealed a high prevalence of off-label and unlicensed drug use in paediatric patients in this hospital, which raises potential issues of unexpected toxicity and adverse drug effects in children by exposing them to drug treatments or regimens that had not been approved by regulatory authorities.