Polymorphisms in Pharmacogenetics of Personalized Cancer Therapy

Therapy process of personalized cancer management covers surgery, chemotherapy, radiation therapy and targeted therapies. The choice of cancer chemotherapeutic agents and doses depends upon the location and stage of tumor, as well as the general state of the patient. On the chemotherapy, radiotherapy, and targeted therapy processes, pharmacogenetics offers customized solutions according to the personal genetic information. Especially for clinicians, genetic information obtained from polymorphism-based pharmacogenetic tests is highly crucial for the better prediction ability of drug response and life-threatening toxic reactions due to the narrow therapeutic index of cancer chemotherapeutic agents. Pharmacogenotyping utilizes different examination strategies, such as single nucleotide polymorphism analysis, somatic/germline mutation analysis and partial/full genome sequencing. The promising effect of pharmacogenetics on the solving of the individual variability in drug response and toxic reactions is being observed with the accumulation of the information that unravel the human genomic variations from large-scale population and multi-parameter-based pharmacogenetic studies of the post-genomic era. Polymorphisms contribute wide variations in human genome and may define how individuals respond to medications, either by changing the pharmacokinetics and pharmacodynamics of drugs or by altering the cellular response to therapeutic agents. To define the effect of polymorphisms on the targets of chemotherapeutics is necessary for the prediction of altered pharmacokinetics of therapeutic agents

Immunopharmacogenomics in Cancer Management

With the unavoidable progress of genomics technologies, “one size fits all” strategy has switched to individual-specific treatment approaches. Hence pharmacogenomics-based personalized cancer medicine has emerged. Promising treatment option immunotherapy includes either “take the brakes off immune system (i.e., checkpoint blockade therapy) or the use of immune cells expanded in an in vitro tumor-free environment’’. Both options have been varied and included unpredictable results. Combination of cancer immunotherapy and pharmacogenomics applications may contribute to solve the complexity of outcome prediction and variations between individuals receiving the same immunotherapeutic treatment. To enhance the tumor immunity and determine cancer patients who response to immunotherapy, classification based on gene polymorphisms in key immunoregulatory molecules including antigen-presenting molecules, immunoglobulins and their receptors, cytokine/chemokines and their receptors, adhesion and costimulatory molecules, toll-like receptors, and intracellular signaling molecules plays a vital role in redirecting or modulating the function of immune cells. Therefore, polymorphisms in immunoregulatory molecules and their impact on immunotherapeutic outcome should be considered in cancer management

MicroRNAs (miRNAs) in Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer in the world and third leading cause of cancer-related deaths in men and women as well. While early screening procedures and removal of small polyps improve the survival rates among the patients, there is still need for new diagnostic and therapeutic approaches for developing more effective treatments. MicroRNAs (miRNAs) are short noncoding RNA fragments, which involve in posttranscriptional regulation of gene expression, and they are shown to involve in tumorigenesis either targeting oncogenes or tumor suppressor genes. Based on the current studies, miRNAs are now suggested as potential biomarkers for CRC diagnosis, prognosis, and therapeutic responses. In this chapter, the latest findings on the role of miRNA in CRC in many aspects are reviewed: diagnosis (role of circular miRNAs in blood and miRNAs from tissue biopsies and their potential role in pathophysiology and diagnosis of CRC), prognosis (miRNAs related with metastasis, recurrence, and survival rates in CRC), and therapeutic responses (role of miRNAs both in chemotherapies and/or in targeted therapies in CRC). In conclusion, miRNAs are promising molecules for diagnosis, prognosis, and therapeutic responses of CRC

DPYD, TYMS and MTHFR Genes Polymorphism Frequencies in a Series of Turkish Colorectal Cancer Patients.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadFluoropyrimidine-based chemotherapy is extensively used for the treatment of solid cancers, including colorectal cancer. However, fluoropyrimidine-driven toxicities are a major problem in the management of the disease. The grade and type of the toxicities depend on demographic factors, but substantial inter-individual variation in fluoropyrimidine-related toxicity is partly explained by genetic factors. The aim of this study was to investigate the effect ofDokuz Eylul University Research Foundatio

The Role of Cyanidin-3-O-glucoside in Modulating Oxaliplatin Resistance by Reversing Mesenchymal Phenotype in Colorectal Cancer.

Background: Epithelial-mesenchymal transition (EMT) plays an important role in the biological and biochemical processes of cells, and it is a critical process in the malignant transformation, and mobility of cancer. Additionally, EMT is one of the main mechanisms contributing to chemoresistance. Resistance to oxaliplatin (OXA) poses a momentous challenge in the chemotherapy of advanced colorectal cancer (CRC) patients, highlighting the need to reverse drug resistance and improve patient survival. In this study, we explored the response of cyanidin-3-O-glucoside (C3G), the most abundant anthocyanin in plants, on the mechanisms of drug resistance in cancer, with the purpose of overcoming acquired OXA resistance in CRC cell lines. Methods: We generated an acquired OXA-resistant cell line, named HCT-116-ROx, by gradually exposing parental HCT-116 cells to increasing concentrations of OXA. To characterize the resistance, we performed cytotoxicity assays and shape factor analyses. The apoptotic rate of both resistant and parental cells was determined using Hoechst 33342/Propidium Iodide (PI) fluorescence staining. Migration capacity was evaluated using a wound-healing assay. The mesenchymal phenotype was assessed through qRT-PCR and immunofluorescence staining, employing E-cadherin, N-cadherin, and Vimentin markers. Results: Resistance characterization announced decreased OXA sensitivity in resistant cells compared to parental cells. Moreover, the resistant cells exhibited a spindle cell morphology, indicative of the mesenchymal phenotype. Combined treatment of C3G and OXA resulted in an augmented apoptotic rate in the resistant cells. The migration capacity of resistant cells was higher than parental cells, while treatment with C3G decreased the migration rate of HCT-116-ROx cells. Analysis of EMT markers showed that HCT-116-ROx cells exhibited loss of the epithelial phenotype (E-cadherin) and gain of the mesenchymal phenotype (N-cadherin and Vimentin) compared to HCT-116 cells. However, treatment of resistant cells with C3G reversed the mesenchymal phenotype. Conclusion: The morphological observations of cells acquiring oxaliplatin resistance indicated the loss of the epithelial phenotype and the acquisition of the mesenchymal phenotype. These findings suggest that EMT may contribute to acquired OXA resistance in CRC. Furthermore, C3G decreased the mobility of resistant cells, and reversed the EMT process, indicating its potential to overcome acquired OXA resistance

Warburg and pasteur phenotypes modulate cancer behavior and therapy.

Energetic pathways combine in the heart of metabolism. These essential routes supply energy for biochemical processes through glycolysis and oxidative phosphorylation. Moreover, they support the synthesis of various biomolecules employed in growth and survival over branching pathways. Yet, cellular energetics are often misguided in cancers as a result of the mutations and altered signaling. As nontransformed and Pasteur-like cells metabolize glucose through oxidative respiration when only oxygen is sufficient, some cancer cells bypass this metabolic switch and run glycolysis at higher rates even in the presence of oxygen. The phenomenon is called aerobic glycolysis or the Warburg effect. An increasing number of studies indicate that both Warburg and Pasteur phenotypes are recognized in the cancer microenvironment and take vital roles in the regulation of drug resistance mechanisms such as redox homeostasis, apoptosis and autophagy. Therefore, the different phenotypes call for different therapeutic approaches. Combined therapies targeting energy metabolism grant new opportunities to overcome the challenges. Nevertheless, new biomarkers emerge to classify the energetic subtypes, thereby the cancer therapy, as our knowledge in coupling energy metabolism with cancer behavior grows.</p

In-silico drug-likeness analysis, ADME properties, and molecular docking studies of cyanidin-3-arabinoside, pelargonidin-3-glucoside, and peonidin-3-arabinoside as natural anticancer compounds against acting receptor-like kinase 5 receptor.

Background:&nbsp;The aim of the study was in-silico drug-likeness analysis, absorption, distribution, metabolism, and excretion (ADME) properties, and molecular docking studies of anthocyanins as natural anticancer compounds against acting receptor-like kinase 5 (ALK5) receptor. Transforming growth factor-β (TGF-β) plays an essential role in various cellular processes. Increased expression of TGF-β and its receptor TGFβR-I (i.e. ALK5) have been associated with poor prognosis in cancer patients.Methods:&nbsp;The drug-likeness activity of anthocyanins was performed using SwissADME tool. Molecular docking studies were carried out by using the Autodock Vina 1.5.6 tool.Results:&nbsp;The results revealed that cyanidin-3-arabinoside (C3A), pelargonidin-3-glucoside (P3G), and peonidin-3-arabinoside (P3A) were able to use both Lipinski's rule of five and Ghose variations. The binding energies of C3A, P3G, and P3A against ALK5 were found as -8.0, -8.3, and -8.4 kcal mol-1, respectively.Conclusion:&nbsp;These selected anthocyanins have shown higher binding energies than known inhibitors to the ALK5 receptor. Further in-vitro and in-vivo studies were strongly recommended to clarify the whole mechanism.</p