Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 16, Issue 2, 2018

Background: Propolis, a honeybee product with plenty of biological properties, has displayed a major role in drug discovery because of tumor cells resistance to chemotherapeutic agents and due to limitations of some drugs. Caffeic Acid Phenethyl Ester (CAPE) derived from propolis also possesses a variety of pharmacological properties including anticancer activity. Breast cancer, the most frequently diagnosed neoplasia and the leading cause of cancer death in women worldwide, is a heterogeneous disease with different clinical presentation, evolution and response to treatment among patients. Objective: Considering the antiproliferative effects of propolis on certain neoplastic cells, an attempt has been made to evaluate its inhibitory activity in the growth of breast cancer cells lines, what may provide new insights for breast cancer therapy. Conclusion: Propolis extracts may be important economically, allowing a relatively inexpensive cancer treatment associated to lower concentrations of drugs. In this review, the activity and mechanisms of action of propolis and CAPE on breast cancer cells are discussed.

Background: Enzymes, proteins, receptors, ion channels and DNA/RNA are among drug targets. DNA-interactive drugs involve alkylation (temozolomide, chlorambucil and cyclophosphamide), intercalation (doxorubicin), DNA breakage (nitroimidazoles), oxidative degradation (bleomycin), code-reading (polyamides and triplex-forming molecules) and stabilization of topoisomerase-DNA complexes (doxorubicin, etoposide, mitoxantrone and SN-38) and G-quadruplexes (perylene, cationic porphyrins and telomestatin). As a non-B DNA structure, G-quadruplexes may form at single-stranded 3'-overhangs of telomeres and the promoters of proto-oncogenes. Telomeric and non-telomeric oligodeoxynucleotides in G-quadruplex conformation exhibit antiproliferative activity against tumour cells and induce apoptosis. However, Gquadruplex motifs are widespread around the chromosome translocation breakpoints in lymphoid cancers. Conclusion: Hairpin/cruciform or slipped-strand DNA structures extruded by inverted and direct repeats, respectively, could be involved in the induction of translocations, deletions, isochromosomes, duplications and inversions in human cancers and genetic diseases as well as the expansion of short nucleotide repeats in hereditary neurological diseases. In addition, there is a significant association between long inverted repeats (LIRs) and the breakpoint regions of gross gene deletions in human cancers and inherited diseases. Thus, this review will focus on non-B DNA structures as candidate drug targets against structural chromosomal instability in various diseases.

Recently, novel drugs that inhibit the enzyme poly (ADP-ribose) polymerase (PARP) based on the concept of synthetic lethality are used for cancer treatment. Three PARP inhibitors (olaparib, rucaparib and niraparib) are approved for the treatment of recurrent ovarian cancer in the US or Europe, while another two (veliparib and talazoparib) showed promising anti-cancer activity. This review aims to summarize the current status of clinical trials on PARP inhibitors and then discusses studies aimed to identify biomarkers for predicting the efficacy of PARP inhibitors.

Background: The ability to kill lymphoid cells with a non-toxic prodrug/gene/ toxin system would be of value in the treatment of lymphoid malignancies and in the regulation of T cells used in adoptive immunotherapy. Objective: In this in vitro study we examined the ability of a novel prodrug/gene/toxin system to produce cytotoxicity in lymphoid cells. The system uses a non-toxic prodrug ethanol, human alcohol dehydrogenase and exerts the toxic action via the prolonged production of acetaldehyde produced within targeted cells. Methods: Raji B cells were transduced with an alcohol dehydrogenase containing lentivirus and then exposed to differing durations of daily ethanol exposure. Cell numbers and viability were assessed by trypan blue exclusion. Results: Individually, ethanol and the ADH gene were non-toxic to Raji B cells. Exposure of ADH transduced cells to ethanol produced prompt growth inhibition and later cell killing that could be negated by the presence of 4-MP the alcohol dehydrogenase inhibitor. At 96 hours exposure to ethanol the number of ADH transduced cells had declined by up to 66% and their total number comprised only 2% of the proliferating untreated control cells. Conclusion: The ethanol ADH acetaldehyde system offers a simple, safe, non-toxic approach to cancer therapy prodrug toxin technology. It may also offer a safe and non-toxic system to control the number and action of T cells used in adoptive immunotherapy.

Background: One of the extensively studied antineoplastic agent is Thymoquinone (TQ). Recent studies show increased level of oxidized low density lipoprotein (oxLDL) among cancer patients. However, how oxLDL is involved in cancer cell survival and growth is poorly understood. The goals of this study were to determine the molecular effects of oxLDL on breast cancer cell (MCF7) growth and how they are modulated by thymoquinone. Methods: A cytotoxicity assay was conducted to determine the IC50 value of TQ. MCF7 cells were exposed to oxLDL for 72 hours in culture, after which phase contrast images were taken. The characteristics of oxLDL-laden MCF7 cells and native MCF7 cells with TQ treatment were studied using proteomic and gene expression assays. Results: Microscopic images showed that oxLDL-laden MCF7 cells were larger than native MCF7 cells. Bright immunofluorescence staining indicated Bcl-2 expression in the cytoplasm and nucleus of oxLDL-laden MCF7 cells. Expression of fatty acid synthase (FASN) and LDL receptor (LDLR) was localized in the cytoplasm of oxLDL-laden MCF7 cells. Native MCF7 cells did not exhibit expression of these proteins. Further investigation showed increased expression of NFΚB, Bcl-2, and LDLR in oxLDL-laden MCF7 cells compared to native MC7 cells. In contrast, FASN expression was lower in oxLDL-laden MCF7 cells compared to native cells. This could be due to availability of extracellular oxLDL and reduced de novo lipid synthesis. Relative gene expression analysis demonstrated downregulation of the EGLN1 gene in oxLDL-laden MCF7 cells, which indicates cell proliferation that is in line with higher expression in Bcl-2 and NFΚB. Similarly, the VAMP4 gene was downregulated, which may indicate the presence of mature granules in oxLDL-laden MCF7 cells. Treatment with TQ inhibited expression of Bcl-2, LDLR and FASN but induced VAMP4 gene expression. Conclusion: Results of this study suggest that TQ modulates oxLDL-induced expression of markers in breast cancer growth.

Background: Estrogen and progesterone play a key role in mammary tumorigenesis of female dogs. Malignant tumors are considered hormone-dependent neoplasms, which may reappear after surgical removal or might spread to other organs such as liver, lymph nodes, and lungs. Objective: The purpose of this study was to evaluate the expression of estrogen receptor α and genes in normal and neoplastic mammary glands of female dogs. Methods: Ten neoplastic tumors (benign and malignant) and 10 normal samples were selected. After RNA extraction and cDNA synthesis, ERα and ERβ genes were amplified by Real-time PCR based on SYBR green related to β-actin reference gene. Results: The obtained Ct and ΔCt values were analyzed by GLM procedure of SAS software v9.2. The results showed that the expression of ERα and ERβ genes in neoplastic cases was over- and down-expressed respectively as compared with normal samples (p < 0.01). Conclusion: The findings indicated that these genes could be used as reference genes for screening and also for early diagnosis of patients, and this method could be helpful for patient selection and monitoring of the anti-estrogen therapy.

Background: Adverse Drug Reactions (ADRs) form one of the leading causes of morbidity and mortality particularly in the elderly population. Alterations in pharmacokinetics and pharmacodynamics with ageing results in increased ADRs which may be novel in respect to the young and may also vary from one older individual to another. These may hence be invaluable in personalized medicine. Objective: The primary objective of this pilot study was to find the occurrence of ADRs in north Indian elderly patients admitted in the Geriatric ward, to analyze its epidemiological attributes and to draw conclusions regarding its implications in designing individualized treatment regimens and plan for larger multi-centric studies. Methods: Elderly patients (>50 years age) admitted in the Geriatric ward were enrolled in this hospital-based, prospective observational study done during the period of September 2014 to September 2015 and June 2016 to October 2017. Adverse drug reaction data was collected based on self-reporting by patients or attendants and/or physician diagnosis. Results: Out of 658 patients (M=388; F=270) admitted in the geriatric ward, 149 ADRs were reported in 103 patients (22.6%). 28 patients (4.2 % of all patients) experienced more than one ADR. Polypharmacy was seen in 98% cases of ADRs. Most commonly reported individual ADR was hypokalemia (13.4%) followed by diarrhea (8.7%). Electrolyte and metabolic abnormalities were the most common ADRs (27.5%) followed by the involvement of gastrointestinal system (18%) and central nervous system (13.4%). 120 (80.5%) ADRs were dose related i.e. Type A ADR and 22 ADRs (14.8%) were immunologic or type B ADRs. In addition, there were 2 cases of ADRs due to drug withdrawal (type E). Category wise, antibiotics were involved in maximum (32.2 % of ADRs) cases followed by diuretics (11.4 % of ADRs), intravenous fluids (10% of ADRs) and antihypertensives (9.4% of ADRs). The Naranjo scale was not applicable in 12.75% of ADRs; mostly due to multiple drugs or interactions being suspected. 55% ADRs were of moderate severity while 11% ADRs were of severe category. ADRs were found to increase the hospital stay by an average of 2 days. Mortality was seen in 4 cases with ADRs. 63% of ADRs were avoidable. Conclusion: A higher than described incidence of ADRs was seen in our study. Polypharmacy was observed as a universal association. Antibiotics and diuretics were the common culprits. A greater fraction of ADRs is avoidable by proper vigilance and adequate monitoring. Awareness about the culprit drugs and associated regional variations may help in avoiding them in the older patients of specific ethnicities. The study highlights the incidence, severity and type of ADRs in the north Indian elderly population and gives platform for large-scale studies in future.

Background: Cancer is a series of different disease (>200 different sub-types) with an identical feature of unlimited growth, invasive and multi-step/multi-level metastasis processes. Objective: Individualized cancer therapies/personalized cancer therapies will undergo a dramatic evolution to cope with this disease diversity and a complexity of tumor genes/biomarkers. Methods: The next generation of personalized cancer therapy must simultaneously contain information of pharmacology (drug sensitivity or drug combination), oncology (tumor etiopathological information), computational network (predictive of cancer risks and therapeutic efficacy), toxicology (adverse side-effects and human mortality), artificial intelligence and patient's desire (decision-aid), especially technology merge. Results: Future multi-functional approach is inevitable. After all, multi-functional personalized cancer therapy (collective and balanced regime/paradigms) might take formation in the future. Conclusion: A reliable, safe, effective and collective platform can be established through further scientific and technical approaches in the clinic.