Combination Treatment with EGFR Inhibitor and Doxorubicin Synergistically Inhibits Proliferation of MCF-7 Cells and MDA-MB-231 Triple-Negative Breast Cancer Cells In Vitro.

The role of the epidermal growth factor receptor (EGFR) in tumor progression and survival is often underplayed. Its expression and/or dysregulation is associated with disease advancement and poor patient outcome as well as drug resistance in breast cancer. EGFR is often overexpressed in breast cancer and particularly triple-negative breast cancer (TNBC), which currently lacks molecular targets. We examined the synergistic potential of an EGFR inhibitor (EGFRi) in combination with doxorubicin (Dox) in estrogen-positive (ER+) MCF-7 and MDA-MB-231 TNBC cell lines. The exposure of MDA-MB-231 and MCF-7 to EGFRi produced an IC50s of 6.03 µM and 3.96 µM, respectively. Dox induced MDA-MB-231 (IC50 9.67 µM) and MCF-7 (IC50 1.4 µM) cytotoxicity. Combinations of EGFRi-Dox significantly reduced the IC50 in MCF-7 (0.46 µM) and MBA-MB 231 (0.01 µM). Synergistic drug interactions in both cell lines were confirmed using the Bliss independence model. Pro-apoptotic Caspase-3/7 activation occurred in MCF-7 at 0.1-10 µM of EGFRi and Dox single treatments, whilst 1 µM Dox yielded a more potent effect on MDA-MB-231. EGFRi and Dox individually and in combination downregulated the EGFR gene expression in MCF-7 and MDA-MB-231 (p < 0.001). This study demonstrates EGFRi's potential for eliciting synergistic interactions with Dox, causing enhanced growth inhibition, apoptosis induction, and downregulation of EGFR in both cell lines.

Inhibition of γH2AX, COX-2 and regulation of antioxidant enzymes in MPP+-exposed SH-SY5Y cells pre-treated with rutin.

Many plant-derived bioactive compounds such as rutin are reportedly effective in attenuating neuronal death in most neurodegenerative disorders. Parkinson's disease (PD) is characterized by the gradual degeneration of dopaminergic neurons in the substantia nigra of the midbrain, and has previously been modelled in-vitro through the specific neurotoxic activity of 1-methyl-4-phenylpyridinium (MPP+) on dopaminergic neurons. Rutin is a bioflavonoid with multiple pharmacological effects, and this study investigated the neuroprotective effects of rutin in the human dopaminergic SH-SY5Y cell line using the neurotoxin MPP+. SH-SY5Y cells pretreated with rutin, were exposed to MPP+ and evaluated for cell viability, nitric oxide (NO), reactive oxygen species (ROS) and antioxidant enzymes activities. In addition, western blot techniques were used to determine the protein expression levels of γH2AX and COX-2. Rutin significantly attenuated MPP+-induced loss of cell viability, mitigated ROS and NO production and inhibited the disruption of antioxidant enzymes activity. It was also observed that rutin significantly reduced protein expression levels of γH2AX and COX-2 in SH-SY5Y cells treated with MPP+. Taken together, findings from this study tend to suggest that rutin is a promising neuroprotective compound for the treatment of PD through its effects on some of the mechanisms that characterize this neurodegenerative disease.

Regulation of AKT/AMPK signaling, autophagy and mitigation of apoptosis in Rutin-pretreated SH-SY5Y cells exposed to MPP.

Accumulating evidence suggest that apoptosis, autophagy and dysregulation of signaling pathways are common mechanisms involved in Parkinson's disease (PD) pathogenesis, and thus development of therapeutic agents targeting these mechanisms may be useful for the treatment of this disease. Although rutin (a bioflavonoid) is reported to have pharmacological benefits such as antioxidant, anti-inflammatory and antitumor activities, there are very few reports on the activity of this compound in 1-methyl-4-phenylpyridinium (MPP+)-induced PD models. Accordingly, we investigated the effects of rutin on apoptosis, autophagy and cell signaling markers (AKT/AMPK) in SH-SY5Y cells exposed to MPP+. Results show reduced changes in nuclear morphology and mitigation of caspase 3/7 and 9 activities in rutin pre-treated cells exposed to MPP+. Likewise, rutin regulated cell signaling pathways (AKT/AMPK) and significantly decreased protein expression levels of cleaved PARP, cytochrome c, LC3-II and p62. Also, rutin significantly increased protein expression levels of full-length caspase 3 in SH-SY5Y cells treated with MPP+. Transmission electron microscope (TEM) images demonstrated a reduction in autophagosomes in rutin-pretreated SH-SY5Y cells exposed to MPP+. These results provide experimental support for rutin's neuroprotective activity against MPP+-induced toxicity in SH-SY5Y cells, which is as a promising therapeutic agent for clinical trials in humans.

An Insight into the Mechanism of Holamine- and Funtumine-Induced Cell Death in Cancer Cells.

Holamine and funtumine, steroidal alkaloids with strong and diverse pharmacological activities are commonly found in the Apocynaceae family of Holarrhena. The selective anti-proliferative and cell cycle arrest effects of holamine and funtumine on cancer cells have been previously reported. The present study evaluated the anti-proliferative mechanism of action of these two steroidal alkaloids on cancer cell lines (HT-29, MCF-7 and HeLa) by exploring the mitochondrial depolarization effects, reactive oxygen species (ROS) induction, apoptosis, F-actin perturbation, and inhibition of topoisomerase-I. The apoptosis-inducing effects of the compounds were studied by flow cytometry using the APOPercentageTM dye and Caspase-3/7 Glo assay kit. The two compounds showed a significantly greater cytotoxicity in cancer cells compared to non-cancer (normal) fibroblasts. The observed antiproliferative effects of the two alkaloids presumably are facilitated through the stimulation of apoptosis. The apoptotic effect was elicited through the modulation of mitochondrial function, elevated ROS production, and caspase-3/7 activation. Both compounds also induced F-actin disorganization and inhibited topoisomerase-I activity. Although holamine and funtumine appear to have translational potential for the development of novel anticancer agents, further mechanistic and molecular studies are recommended to fully understand their anticancer effects.

Cytotoxicity Potential of Endophytic Fungi Extracts from Terminalia catappa against Human Cervical Cancer Cells.

Endophytic fungi are potential sources of novel bioactive metabolites from a natural product drug discovery perspective. This study reports the bioactivity-directed fractionation of the secondary metabolites of the ethyl acetate extract of a fermentation culture of endophytic fungi from Terminalia catappa which were then evaluated for their cytotoxicity against human cervical cancer (HeLa) cells and human foreskin fibroblast (HFF) cells. Furthermore, apoptosis was determined using the Annexin V/propidium iodide (PI) flow cytometry assay. Endophyte extracts N2, N7, N8, N97, N169, and N233 were obtained from Trichoderma sp, Phoma sp, Phomopsis phyllanticola, Fusarium oxyporum, Collectotrichum sp, and Cryptococcus flavescens, respectively. The N97 extract was most active with a 50% inhibitory concentration (IC50) of 33.35 µg/ml. A 50% cytotoxic concentration (CC50) of 268.4 µg/ml was obtained with HFF cells and the selectivity index (SI) was 8.01. The percentages of cell populations were increased at late apoptosis (Annexin+/PI+), with the percentages of 27.4 ± 0.3 and 19.2 ± 0.01 obtained, respectively, for 50 µg/ml and 80 µg/ml of the N97 extract and 2.1 ± 0.1 obtained for the control in late apoptosis (Annexin V+/PI+) . Moreover, a higher reduction in the percentage of viable cells was observed in the HeLa control cells (93.6 ± 0.3), but the percentages of viable HeLa cells were 37 ± 0.05 and 45 ± 0.1, respectively, for the 50 µg/ml and 80 µg/ml treatments with the N97 extract. Also, the percentages of 34.7 ± 0.1 and 33.9 ± 0.4 were, respectively, obtained for 50 µg/ml and 80 µg/ml compared to the control with 4.6 ± 0.2, in early apoptosis (Annexin V+/PI-). These findings highlight the anticancer potential of the N97 extract of endophytic fungi from Terminalia catappa, which is mediated through apoptosis and presumably also attenuation of chemoresistance.

Attenuation of Endoplasmic Reticulum Stress, Impaired Calcium Homeostasis, and Altered Bioenergetic Functions in MPP+-Exposed SH-SY5Y Cells Pretreated with Rutin.

Parkinson's disease (PD) is a common neurodegenerative disorder that affects approximately 1% of the population over the age of 65 years. While treatment options for PD are limited, reports show that plant-derived bioactive compounds such as rutin possess numerous pharmacological benefits, including antioxidant and antiapoptotic activities. This study aimed to investigate the potential role of rutin in MPP+-treated SH-SY5Y neuroblastoma cells, an established cell model of PD. Our findings reveal increased concentrations of Ca2+ and endoplasmic reticulum (ER) stress as well as impaired mitochondrial membrane potential and bioenergetic status in SH-SY5Y cells treated with MPP+ only. This is demonstrated by a significant reduction in the expression levels of BiP, significantly reduced basal respiration, maximal respiration, and spare respiratory capacity as well as a significant increase in the expression levels of CHOP; however, these effects were significantly attenuated following pretreatment with rutin. Also, rutin significantly improved basal and compensatory glycolysis as a response to an impaired oxidative phosphorylation system triggered by MPP+, characterized by deficient ATP production. In conclusion, our findings provide the first evidence on the ability of rutin to maintain Ca2+ homeostasis, inhibit ER stress, and protect the mitochondria in MPP+-treated SH-SY5Y cells.

GRP78/BIP/HSPA5 as a Therapeutic Target in Models of Parkinson's Disease: A Mini Review.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by selective loss of dopamine neurons in the substantia nigra pars compacta of the midbrain. Reports from postmortem studies in the human PD brain, and experimental PD models reveal that endoplasmic reticulum (ER) stress is implicated in the pathogenesis of PD. In times of stress, the unfolded or misfolded proteins overload the folding capacity of the ER to induce a condition generally known as ER stress. During ER stress, cells activate the unfolded protein response (UPR) to handle increasing amounts of abnormal proteins, and recent evidence has demonstrated the activation of the ER chaperone GRP78/BiP (78 kDa glucose-regulated protein/binding immunoglobulin protein), which is important for proper folding of newly synthesized and partly folded proteins to maintain protein homeostasis. Although the activation of this protein is essential for the initiation of the UPR in PD, there are inconsistent reports on its expression in various PD models. Consequently, this review article aims to summarize current knowledge on neuroprotective agents targeting the expression of GRP78/BiP in the regulation of ER stress in experimental PD models.

Patterns of copy number alterations in primary breast tumors of South African patients and their impact on functional cellular pathways.

Breast cancer is the most common and the leading cause of female mortality among South African (SA) women. Several non­biological and biological risk factors may be attributed to their observed high mortality rate; however, the molecular profiles associated with their breast tumors are poorly characterized. The present study examined the patterns of genome-wide copy number alterations (CNAs) and their potential impact on functional cellular pathways targeted by cancer driver genes in patients with breast cancer from the Western Cape region of SA. Array-comparative genomic hybridization analysis, performed in 28 cases of invasive breast cancer, revealed a mean number of 8.68±6.18 CNAs per case, affecting primarily the Xp22.3 and 6p21-p25 cytobands (57.14% of the cases), followed by 19p13.3-p13.11 (35.7%), 2p25.3-p24.3, 4p16.3-p15.3, 8q11.1-q24.3 and 16 p13.3-p11.2 (32.14%). Functional enrichment analysis of genes and microRNA targets mapped in these affected cytobands revealed critical cancer-associated pathways, including fatty acid biosynthesis and metabolism, extracellular matrix-receptor interaction, hippo and tumor protein p53 signaling pathways, which are regulated by known cancer genes, including CCND1, CDKN1A, MAPK1, MDM2, TP53 and SMAD2. An inverse correlation was observed among the number of CNAs and tumor size and grade; CNAs on the 4p and 6p cytobands were also inversely correlated with tumor grade. No association was observed in the number of CNAs and/or the affected cytobands and the different ethnic groups of the SA patients, indicating that their tumor genome is affected by CNAs, irrespectively of their genetic descent. Additional genomic tumor profiling in SA and other Sub-Saharan African patients with breast cancer is required to determine the associations of the CNAs observed with prognosis and clinical outcome.

Rutin as a Potent Antioxidant: Implications for Neurodegenerative Disorders.

A wide range of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases, share common mechanisms such as neuronal loss, apoptosis, mitochondrial dysfunction, oxidative stress, and inflammation. Intervention strategies using plant-derived bioactive compounds have been offered as a form of treatment for these debilitating conditions, as there are currently no remedies to prevent, reverse, or halt the progression of neuronal loss. Rutin, a glycoside of the flavonoid quercetin, is found in many plants and fruits, especially buckwheat, apricots, cherries, grapes, grapefruit, plums, and oranges. Pharmacological studies have reported the beneficial effects of rutin in many disease conditions, and its therapeutic potential in several models of NDs has created considerable excitement. Here, we have summarized the current knowledge on the neuroprotective mechanisms of rutin in various experimental models of NDs. The mechanisms of action reviewed in this article include reduction of proinflammatory cytokines, improved antioxidant enzyme activities, activation of the mitogen-activated protein kinase cascade, downregulation of mRNA expression of PD-linked and proapoptotic genes, upregulation of the ion transport and antiapoptotic genes, and restoration of the activities of mitochondrial complex enzymes. Taken together, these findings suggest that rutin may be a promising neuroprotective compound for the treatment of NDs.

Effects of Fucoidan and Chemotherapeutic Agent Combinations on Malignant and Non-malignant Breast Cell Lines.

OBJECTIVES: Breast cancer is a leading cause of death among women in both developed and Third World countries. Fucoidan is a natural plant metabolite produced by brown seaweeds with proven anticancer potential. This study determined the cytotoxic, apoptotic and cell cycle effects of fucoidan alone and in combination with first-line anticancer drugs (cisplatin, doxorubicin and taxol) in MCF-7 breast cancer cells and non-malignant MCF-12A breast epithelial cells as control. METHODS: Cytotoxicity was evaluated using the MTT reduction assay. Cell cycle distribution and apoptosis were assessed by flow cytometry using Annexin VFITC/PI and Hoechst 33342 staining, and caspases-3, -7 and -9 activation. RESULTS: Fucoidan alone was significantly more cytotoxic to MCF-7 breast cancer cells compared to the MCF-12A non-cancerous breast epithelial cell line. In MCF-7 cells, the presence of fucoidan caused cell cycle arrest at G1 with accumulation of cells in the sub-G1 phase with the activation of caspases-3,-7 and -9. Furthermore, combination of fucoidan with the standard chemotherapeutic agents-cisplatin, doxorubicin and taxol-significantly enhanced the cytotoxicity of these drugs and accumulation of cells in the G2/M and sub-G1 phases, and induction of apoptosis. No significant differences were observed between fucoidan-treated and untreated MCF-12A cells with respect to cytotoxicity and cell cycle distribution profiles. By contrast, in non-cancerous MCF-12A cells, fucoidan attenuated the toxicity of doxorubicin and cisplatin in combination by increasing their IC50 values. This effect was not demonstrated with the taxol combination. CONCLUSIONS: Fucoidan is an effective antitumor agent, either alone or in combination with cisplatin, doxorubicin and taxol in MCF-7 breast cancer cells. Drug combinations that discriminate between cancerous and non-cancerous cells afford a plausible and viable strategy of attaining therapeutic efficacy and avoiding possible toxicity and side effects. These findings suggest that fucoidan is a promising candidate for cancer combination therapies.

Isolation and antioxidant activity of flavonoids from Holarrhena floribunda (G.don) leaves.

Bioactive polyphenolics are ubiquitously present in plants and may play an important role in the prevention and management of certain human diseases. Three known flavonoids viz Kaemperol-3-O-rutinoside (1), quercetin-3-O-glucoside (2) and kaemperol-3-O-glucoside (3) and inseparable mixture (1:1) of quercetin-3-O-glucose/galactose (4) were isolated, and identified for the first time from Holarrhena floribunda. The antioxidant capacity using the ORAC, FRAP and TEAC assays and inhibition of lipid peroxidation were measured for isolated flavonoids. The result showed that compounds 2 and 4 showed significantly increased ORAC, TEAC, and FRAP activities with low pro-oxidant potential as well as improved lipid peroxidation inhibition levels when compared to compounds 1 and 3. The most active compounds were found to be flavonoids with a quercetin basic structure. These results imply that the isolated flavonoid glycosides are responsible for the antioxidant activity of the plant leaves and it forms the scientific basis for its traditional usage.

Copy Number Analysis of the DLX4 and ERBB2 Genes in South African Breast Cancer Patients.

Breast cancer is one of the main causes of cancer death among South African women. Although several risk factors can be attributed to the observed high mortality rate, the biology of the tumors is not extensively investigated. Copy number gain of the DLX4 homeobox gene has been observed in breast cancer in association with poor prognosis and specific racial groups. Therefore, we aimed to assess the copy number and prognostic role of DLX4 in breast cancer from South African patients. Due to the co-location of ERBB2 and DLX4 in the 17q21 region, its copy number was also evaluated. Our results in the analysis of 66 cases demonstrated copy number gains of DLX4 and ERBB2 in 24.1 and 29.7% of the cases, respectively. Linear regression analysis showed no dependency between the copy number alterations in these genes. Although not significant, patients with DLX4 and ERBB2 gains presented a higher frequency of advanced-grade tumors. In addition, copy number alterations of these genes were not significantly differently observed in the 3 main racial groups of the Western Cape population: Colored, White, and Black. These findings indicate that gains of DLX4 and ERBB2 occur in South African breast cancer patients irrespectively of their race and factors known to influence prognosis.

Melamine contamination in nutritional supplements--Is it an alarm bell for the general consumer, athletes, and 'Weekend Warriors'?

BACKGROUND: Nutritional supplements are used or experimented with by consumers, notably these are; competitive and recreational athletes of all ages, and 'weekend warriors'. As a consequence the supplement industry has grown to meet the increasing demand. A Global Industry Analysts Inc. report indicates that the herbal supplement market has not declined during the worldwide recession, but in fact exhibited steady growth over the period 2008 to 2009. It is anticipated that the market will reach US$93.15 billion by the year 2015. These supplements may contain adulterated substances that may potentially have harmful short - and long-term health consequences to the consumer. "Scrap Melamine" is such an example, which has been implicated in the kidney failure and death of several cats, dogs and pigs. In China in 2008, reports described very severe health effects in infants and young children. At the time over 294,000 infants were screened and diagnosed with urinary tract stones and sand-like calculi associated with melamine in milk products, of which 50,000 infants were hospitalised, and at least six associated deaths, recorded. The extent that melamine contamination occurs in nutritional supplements is not known. Therefore, the aim of this study was to determine whether commercially available nutritional and traditional supplement products contain melamine, even though they are not declared by the manufacturer on the product label. METHODS: A total of 138 nutritional supplements products were obtained from (i) direct purchases from shops, pharmacies and outlets, (ii) directly from consumers, and (iii) from suppliers, manufacturers and distributors. The products were laboratory analysed for melamine, using Tandem Liquid Chromatography Mass Spectrometry. RESULTS: Forty-seven % of all the products (n = 138) tested positive for melamine. Eight-two % of the South African produced products (n = 27) tested positive and 58 % of the products imported into South Africa (n = 50) tested positive. The median concentration estimate for melamine in the products tested were, 6.0 µg/g for the 138 supplements tested, 8.9 µg/g for South African produced products, and 6.9 µg/g for products imported into South Africa. CONCLUSION: The melamine (undeclared on product label) levels detected in the nutritional supplements products investigated were within the Tolerable Daily intake (TDI) limit guidelines of 200 µg/g as set by WHO and others. Melamine over exposure within the context of the nutritional supplements consumption in the products investigated should not be of concern to the consumer provided the recommended guidelines of daily product use are adhered to. Further investigation is warranted to determine, (i) the link of melamine as (part) substitute for the perceived total declared protein content on the product label, (ii) cyanuric and uric acid presence in the supplement products that could form chemical-complex formation with melamine and/or analogues that could cause adverse health effects.

In Vitro and In Vivo Biochemical Evaluations of the Methanolic Leaf Extract of Garcinia kola.

Garcinia kola Heckel (Guttiferae) leaves have received limited scientific attention despite their traditionally acclaimed medicinal properties. The scavenging ability of the methanolic leaf extract (MLE) of G. kola was assayed for hydroxyl radical (OH(•)), superoxide anion (O2 (-)), 1,1-diphenyl-2-picrylhydrazyl (DPPH), azinobis-3-ethyl-benzothiazoline-6-sulfonic acid (ABTS(•+)), and lipid peroxidation (LP) activity in egg yolk, rat liver, and brain homogenates. Total phenolic and flavonoid contents of the extract were also evaluated. Group I animals were given oral doses of water, whereas Group II and Group III animals received 100 and 200 mg/kg body weight (bw) MLE, respectively, for 14 days. Plasma glucose, magnesium, γ-glutamyltransferase (GGT/γGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and urea were evaluated. Hepatic reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD), LP, and liver histopathological appearance were also assessed. The extract scavenged OH(•), O2 (-), DPPH, and ABTS(•+) and inhibited LP in egg yolk, rat liver, and brain homogenates. Furthermore, oral administration of the extract showed no adverse effects on hepatic and renal function tests. Increased hepatic GSH and nonsignificant changes in LP, GPx and SOD activities, and liver histology were observed. These results suggest that G. kola leaves have antioxidant activities which may have application in traditional medicine.

Evaluation of antioxidant, antimutagenic, and lipid peroxidation inhibitory activities of selected fractions of Holarrhena floribunda (G. Don) leaves.

Exposure to environmental pollutants often leads to an upsurge in the production of reactive oxygen species (ROS). ROS oxidize cellular fatty acids to produce lipid peroxyl radicals, subsequently transformed into lipid peroxides, which decrease membrane fluidity and increase the activity of various enzymes implicated in degenerative diseases and cancer formation. Edible plants that contain exogenous compounds like curcumeroid, ß-carotene, turmeric, and so on, protect the aerobic cells from oxidation of free radicals. This study thus evaluates antioxidant and antimutagenic activities of ethyl acetate, aqueous and methanolic fractions of Holarrhena floribunda leaves. Inhibitory activities of the ethyl acetate fraction on Fe(2+)-induced lipid peroxidation in hen egg yolk; rat liver and brain tissues were also evaluated. The Allium cepa root assay was used to evaluate antimutagenic activity. Results showed that the ethyl acetate scavenged DPPH, OH•, and •O2(-) much stronger than other fractions, as evidenced by its lowest respective IC50 values. All the fractions displayed antimutagenic activities against cyclophosphamide-induced chromosomal aberrations. Likewise, all the fractions induced a reduction in mitotic index, a hallmark of cytotoxicity in the root meristem of Allium cepa. The decrease in mitotic index was most profound for the ethyl acetate fraction, which also demonstrated a significant lipid peroxidation inhibitory activity in the liver and brain homogenates, but not in egg yolk, compared with the ascorbic acid standard. In general, the results suggest that the ethyl acetate fraction might contain beneficial phytochemicals that should be explored as novel candidates for preclinical drug development.

Criteria to facilitate the implementation of woman-centred care in childbirth units of Limpopo Province, South Africa (Part 2).

BACKGROUND: Facilitation of mutual participation, respectful and egalitarian relationship between the mother and the midwife during childbirth is a critical aspect. This article delineated the criteria that would facilitate the implementation of woman-centred care in childbirth units of the Limpopo Province in South Africa, following a concept analysis described in Part 1. Empirical referents or indicators were used to measure the concept woman-centred care and to validate its existence in reality. These empirical referents were referred to as measurable properties that further verified the concept. OBJECTIVE: The objective of this article was to formulate criteria that would facilitate implementation of woman-centred care in childbirth units of Limpopo Province in South Africa. METHOD: Criteria to facilitate the implementation of woman-centred care were formulated by the gathering of information about the topic under review and the use of resources to define the key elements of the criteria which were integrated into the Batho Pele principles. The criteria were then validated by selecting with a vested interest in the successful development and implementation of the criteria. RESULTS: Criteria were formulated to facilitate the implementation of woman-centred care that was integrated within the framework of Batho Pele principles. CONCLUSION: These formulated criteria for woman-centred care will be used as an institutional self-evaluation tool to enhance implementation of the Batho Pele principles in childbirth units. These criteria will give direction and provide guidelines for the performance of midwifery staff and will also help supervisors to guide staff to improve performance.

Optimization and preclinical design of genetically engineered viruses for human oncolytic therapy.

INTRODUCTION: Oncolytic viruses (OVs) occupy a strategic niche in the dynamic era of biological and gene therapy of human cancers. However, the use of OVs is the subject of close scrutiny due to impediments such as the insufficiency of patient generalizations posed by heterogeneous tumor responses to treatment, inherent or potentially lethal viral pathogenicities, unanticipated host- or immune-related adverse effects, and the emergence of virus-resistant cancer cells. These challenges can be overcome by the design and development of more definitive (optimized, targeted, and individualized) cancer virotherapeutics. AREAS COVERED: The translation of current knowledge and recent innovations into rational treatment prospects hinges on an iterative loop of variables pertaining to genetically engineered viral oncolytic efficacy and safety profiles, mechanism-of-action data, potencies of synergistic oncolytic viral combinations with conventional tumor, immuno-, chemo-, and radiation treatment modalities, optimization of the probabilities of treatment successes in heterogeneous (virus-sensitive and -resistant) tumor cell populations by mathematical modeling, and lessons learned from preclinical studies and human clinical trials. EXPERT OPINION: In recent years, it has become increasingly clear that proof-of-principle is critical for the preclinical optimization of oncolytic viruses to target heterogeneous forms of cancer and to prioritize current concerns related to the efficacy and safety of oncolytic virotherapy.

Optimizing molecular-targeted therapies in ovarian cancer: the renewed surge of interest in ovarian cancer biomarkers and cell signaling pathways.

The hallmarks of ovarian cancer encompass the development of resistance, disease recurrence and poor prognosis. Ovarian cancer cells express gene signatures which pose significant challenges for cancer drug development, therapeutics, prevention and management. Despite enhancements in contemporary tumor debulking surgery, tentative combination regimens and abdominal radiation which can achieve beneficial response rates, the majority of ovarian cancer patients not only experience adverse effects, but also eventually relapse. Therefore, additional therapeutic possibilities need to be explored to minimize adverse events and prolong progression-free and overall response rates in ovarian cancer patients. Currently, a revival in cancer drug discovery is devoted to identifying diagnostic and prognostic ovarian cancer biomarkers. However, the sensitivity and reliability of such biomarkers may be complicated by mutations in the BRCA1 or BRCA2 genes, diverse genetic risk factors, unidentified initiation and progression elements, molecular tumor heterogeneity and disease staging. There is thus a dire need to expand existing ovarian cancer therapies with broad-spectrum and individualized molecular targeted approaches. The aim of this review is to profile recent developments in our understanding of the interrelationships among selected ovarian tumor biomarkers, heterogeneous expression signatures and related molecular signal transduction pathways, and their translation into more efficacious targeted treatment rationales.

Will the new Consumer Protection Act prevent harm to nutritional supplement users?

BACKGROUND. There is no clear distinction between the regulation of food, supplements and medicines in South Africa. Consequently, grey areas exist in implementing the legislation, particularly in the supplement industry. The increase in supplement sales in South Africa can be attributed to aggressive marketing by manufacturers whose claims are not always supported by published peer-reviewed evidence. Such claims often go unchecked, resulting in consumers being mislead about the role of supplements. As a result of poor regulation, contaminants or adulterants in supplements may also cause insidious effects unrelated to the listed ingredients. AIM. To assess the regulations, legislation, and claims associated with nutritional supplement products in South Africa. METHOD. Peer-reviewed literature and the relevant South African statutes were consulted. RESULTS. The National Health Act incorporates the Medicine Control Council, which is charged with ensuring the safety, quality and effectiveness of medicines, and related matters, including complementary/alternative medicines. The South African Institute for Drug-Free Sport and Amendment Act provides for testing athletes for using banned substances, but currently does not concern itself with monitoring nutritional supplements for contaminants or adulterants that may cause a positive drug test, which has implications for sports participants and also the health of the general population. The implementation of the Consumer Protection Act 68 of 2008 (CPA) could protect consumer rights if it is administered and resourced appropriately. CONCLUSION. The CPA should promote greater levels of policy development, regulatory enforcement, and consumer education of South Africa's supplement industry.

Implications of endoplasmic reticulum stress, the unfolded protein response and apoptosis for molecular cancer therapy. Part II: targeting cell cycle events, caspases, NF-κB and the proteasome.

BACKGROUND: Endoplasmic reticulum stress (ERS), the unfolded protein response (UPR) and apoptosis signal transduction pathways are fundamental to normal cellular homeostasis and survival, but are exploited by cancer cells to promote the cancer phenotype. OBJECTIVE: Collateral activation of ERS and UPR role players impact on cell growth, cell cycle arrest or apoptosis, genomic stability, tumour initiation and progression, tumour aggressiveness and drug resistance. An understanding of these processes affords promising prospects for specific cancer drug targeting of the ERS, UPR and apoptotic pathways. METHOD: This review (Part II of II) brings forward the latest developments relevant to the molecular connections among cell cycle regulators, caspases, NF-κB, and the proteasome with ERS and UPR signalling cascades, their functions in apoptosis induction, apoptosis resistance and oncogenesis, and how these relationships can be exploited for targeted cancer therapy. CONCLUSION: Overall, ERS, the UPR and apoptosis signalling cascades (the molecular therapeutic targets) and the development of drugs that attack these targets signify a success story in cancer drug discovery, but a more reductionist approach is necessary to determine the precise molecular switches that turn on antiapoptotic and pro-apoptotic programmes.