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Abstract |
Pancreatic cancer (PC) is the 4th leading cause of cancer in the US and the survival rate beyond 5 years is below 9%; the lowest of any cancer1. Pancreas and liver cancers are projected to surpass breast, prostate, and colorectal cancers to become the second and third leading causes of cancer-related death by 2030, respectively2. There are two types of pancreatic cancer: exocrine tumors (the tumor happens where the cells produce enzyme to digest food) and endocrine tumors (the tumor happens where the cells produce insulin to regulate blood sugar). About 95 percent of pancreatic cancers begin in the exocrine cells of the pancreas3. The causes of pancreatic cancer remain unknown, tobacco, alcohol, family history and high -cholesterol diet are contributing factors. The progression from normal epithelium to pancreatic cancer begins with the accumulation of activation of oncogene KRAS and then inactivation of tumor suppressor genes—for example p16 (also known as CDKN2A), SMAD4 (also known as DPC4), and p53 (also known as TP53)4-5 evolve via pancreatic intraepithelial neoplasias (PanINs). KRAS mutations is responsible for 75-90% of pancreatic cancer patients and start very early in the development of pancreatic cancer6-9. The well-validated role of mutationally activated RAS genes in driving cancer development and growth has stimulated comprehensive efforts to develop therapeutic strategies to block mutant RAS function for cancer treatment. Disappointingly, despite more than three decades of research effort, clinically effective anti-RAS therapies have remained elusive, prompting a perception that RAS may be undruggable10. PC is usually diagnosed by a combination of medical imaging techniques such as ultrasound computed tomography, CT scan with IV contrast, blood tests, and examination of tissue samples (biopsy). At this time, the best progress for this disease is to diagnose in the early stages. Phenomics is an branch of biology responsible for the measurement of phenomes—the physical and biochemical characteristic of organisms as they change correlated to genetic environmental factors11. Traditional biological experiments, such as GWA (genome-wide association) studies, is selecting a phenotype and then attempting to associate biological differences within a population. The unequivocal phenotype is what patients and clinicians wish to predict. At present, none phenomics studies have been applied to drug therapy. Detailed electronic medical record (EMR) data will allow for large-scale phenomics studies, when paired with GWA studies or other biological databases12. Metabolomes are defined as all compounds generated by living organisms during their life cycles and reflect the function of the organisms as a whole13. Metabolomics analysis can be applied to both in vitro and in vivo specimens by using body fluids, cells or tissues. Comparing the different result of metabolomics analysis of the pancreatic cancer patient and healthy people can provide the reference of the detection of pancreatic cancer. The two most popular techniques are nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) coupled with gas chromatography, liquid chromatography or capillary electrophoresis.14-16 Although cross sectional imaging tests such as abdominal ultrasound (US), computerized tomography (CT-scan), magnetic resonance imaging (MRI), endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) have been developed to detect the disease, none of them works for the early stage tumor.17-19 Biomarkers lack enough specificity to make difference between PC and diseases such as pancreatitis and cholangitis.17 Since no single molecule has been shown to be specific enough for the discrimination of patients with early PC, some study groups have used multiple logistic regression analysis to compare PC patients with healthy controls. a statistical diagnostic model was generated.20 In addition to serum, other biofluids such as bile and pancreatic fluids have been used to study metabolic profiles for the diagnosis of early PC.21 The saliva metabolites profiles showed higher concentrations of most of the metabolites detected in pancreatic, breast and oral cancer compared with those with periodontal disease and control diseases. This result indicates that cancer-specific signatures are contained in saliva metabolites. Multiple logistic regression models showed high area under the receive operating characteristic curves (AUCs) to discriminate healthy controls from each disease. The AUCs were 0.993 for pancreatic cancer, and 0.969 for periodontal diseases. The accuracy of the models was also high, with cross-validation AUCs of 0.994, and 0.954, respectively. Even these correlations significant and promising, but they are small and not sufficient to change current clinical practice and more studies are needed.21-22 No diagnostic tests for the screening of pancreatic cancer has been identified thus far and none of the biomarkers has yet to be proven useful for this purpose17. Genomics is a discipline in genetics that applies recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the function and structure of genomes.23 Genetics represents a constant in any biological system compared with metabolomes and phenomics. DNA of the healthy individuals and pancreatic cancer patients were analyzed, and it was found that pancreatic cancers contain an average of 63 genetic alterations, most of them point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors24. Surgery is the only possibility for a curative treatment but is a limited option only available to 15-20% of PC patients present with localized and potentially curable tumors25. As a result, chemotherapy and radiation therapy plays an important role throughout PC treatment. Radiation therapy is quite helpful for treating the exocrine cancer and, it can help relieve the patients’ pain. In patients not suitable for curative surgery, chemotherapy and radiationtherapy are primary ways to extend life or improve its quality. Endocrine cancer does not respond well to radiation therapy. What is more it will cause unpleasant side effects such as skin changes, fatigue, nausea, and other side-effects26. Currently, there are four major first-line drugs approved for the treatment of pancreatic cancer: FOLFIRINOX, erlotinib, gemcitabine, and mitomycin C. There are also other drugs, like Platinum agents (Cisplatin and Oxaliplatin), humanized antibody Keytruda, and Taxanes. FOLFIRINOX and gemcitabine act by replacing pyrimidine and cytidine, respectively, during the biosynthesis of nucleic acids and DNA replication. As a result, tumor growth is arrested by false nucleoside incorporation induced cell death. As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status26. Mitomycin C, oxaliplatin and cisplatin are DNA cross-linking agents, which can react with two different positions in DNA, halt DNA synthesis and lead to apoptosis27. Erlotinib is a small molecule human epidermal growth factor receptor 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, preventing the growth factor and receiver from being phosphorylated, effectively disrupting the signaling pathway28. The molecular action of irinotecan occurs by trapping a subset of topoisomerase-1-DNA cleavage complexes, leading to inhibition of both DNA replication and transcription29. The principal mechanism of action of the taxane class of drugs is the disruption of microtubule function27. Keytruda used in cancer immunotherapy, can block protective mechanism of cancer cells and thereby, allows the immune system to destroy them30. However, regardless of whether these drugs are used alone or in combination, none have been effective in significantly improving overall survival rates. This disparity, compared to other cancer types, has led to the projection that pancreatic cancer will become the second most deadly cancer in the United States by 2030, surpassed only by lung cancer31. Any improvements in treatment will come as a much-needed reprieve to patients diagnosed with this uniquely-challenging and lethal disease. Advances will come from more effective and specific chemotherapeutic agents. The marine environment with its exceptional biodiversity has yielded diverse chemical space and serves as a rich source of novel compounds with significant therapeutic promise. Discorhabdin alkaloids are the main metabolites of Latrunculia sponge and all the published discorhabdins showed different ranges of cytotoxicity to different cancer cells.32 Thus, we hypothesis that new discorhabdins from Latrunculia sponge could be a lead for pancreatic cancer. Instead of isolating strictly using other low-throughput chemical techniques or bioassays alone which is time consuming, Molecular Ion Networking (MoIN) to isolate new and novel compounds was applied. A new class of pyrroloiminoquinone alkaloids possessing a highly strained multi-bridged ring system, discovered from Latrunculia (Latrunculia) austini Samaai, Kelly & Gibbons, 2006 (class Demospongiae, order Poecilosclerida, family Latrunculiidae) recovered during a NOAA deep-water exploration of the Aleutian Islands. The molecule was identified with the guidance of MS, NMR, and Molecular Ion Networking (MoIN) analysis. The structure of aleutianamine was determined using extensive spectroscopic analysis in conjunction with computationally-assisted quantifiable structure elucidation tools. Aleutianamine exhibited potent and selective cytotoxicity toward solid tumor cell lines including PC(PANC-1) with an IC50 of 25 nM and colon cancer (H116) with IC50 of 1 µM and represents a potent and selective candidate for advanced preclinical studies. Plant-microbiome association studies have revealed a unique relationship between the host plants and their microbiome. This relationship involves significant benefits for the plant through protection from fungi, bacteria, herbivores and insects; however, at the same time overgrowth of an endophyte can cause harm to the plant33. The role of natural products in microbiome-plant associations and the overall success of plants remains a highly complex and relatively unexplored field34-35. We serendipitously discovered that plant microbiome Bacillus. amyloliquefaciens cultured from American sycamore produced rapamycin and was regulated seasonally and plant organ specific differently by platanoside isolated from American sycamore (Platanus occidentalis L.). Although that B. amyloliquefaciens generates diversity of metabolites from polyketides to triterpenes, influence many expects from pathogenic defense to growth promotion, B. amyloliquefaciens generating rapamycin and regulated by host metabolites was expected. Here, we show that previously characterized rapamycin was generated by B. amyloliquefaciens inhabiting in xylem of American sycamore. We demonstrate that the potent antibiotics platanosides found in the healthy sycamore leaves appear to play a clear regulator function of the B. amyloliquefaceins. It has been reported that when the Target of Rapamycin (TOR) is inhibited in plants treated with rapamycin, it will promote autophagy of the cells and differentiation of xylem tracheary elements as well as extend the life-expectancy of the plant36. These results revealed that rapamycin generated by B. amyloliquefaciens appears to play a key role in the development of vascular tissue to transport water in this species of tree, promote autophagy of autumn leaves thus recovering nutrients and contribute to sycamore unique longevity. It also displayed how P. occidentalis controls the growth of B. amyloliquefaciens subsp. plantarum through the concentration of platanoside to avoid the potential harm caused by the overgrowth of B. amyloliquefaciens subsp. plantarum. The metabolites from endophytes and hosts mediate the interaction to realize the success of this species. The chronic liver disease caused by xenobiotics and viral infection will eventually lead to liver cancer; the second most common cancer in the world. In 2018, WHO reported that around 788,000 people die from primary liver cancer every year. It is also reported that from 1999 to 2015, deaths from liver cancer in the US increased by 60% while deaths from other cancers decreased by 26%. Levels of both hepatitis testing and treatment are still extremely low in most regions of the world drugs still play a vital role in controlling liver disease. Highly oxygenated triterpenoids and dibenzocyclooctadiene lignans isolated from plants of the genera Schisandra and Kadsura have revealed a variety of important biological activities including potent anti-HIV 37, anti-HBV 38, and cytotoxic properties39-42. Two clinically used drugs for liver disease dimethyl bicarboxylate and bicyclol are the structurally modified molecules isolated from Schisandra and Kadsura. We hypothesized that unreported hepatoprotective triterpenoids and dibenzocyclooctadiene lignans from Kadsura can be drug candidates for the liver disease. Their 2D structures and relative configurations have been successfully elucidated by NMR spectroscopic methods. Assignment of their absolute configurations is critical since it influences their bioactivities and is essential for future efforts focused on synthesis and medicinal chemistry applications. Herein, we report an integrated analysis to comprehensively assign the absolute configurations of four new schiartane-type nortriterpenoids and three novel dibenzocyclooctadiene lignans using a combination of methods. |
MEDICA, MUSC Institutional Repository
