Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)-cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer.
Matched MeSH terms: Triple Negative Breast Neoplasms/pathology*
Microtubule Targeting Agents (MTAs) induce cell death through mitotic arrest, preferentially affecting rapidly dividing cancer cells over slowly proliferating normal cells. Previously, we showed that Methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) acts as a potential MTA. In this study, we demonstrated that MBIC exhibits greater toxicity towards non-aggressive breast cancer cell-line, MCF-7 (IC50 = 0.73 ± 0.0 μM) compared to normal fibroblast cell-line, L-cells (IC50 = 59.6 ± 2.5 μM). The IC50 of MBIC against the aggressive breast cancer cell-line, MDA-MB-231 was 20.4 ± 0.2 μM. We hypothesized that the relatively high resistance of MDA-MB-231 cells to MBIC is associated with p53 mutation. We investigated p53 and three of its downstream proteins: survivin, cyclin dependent kinase (Cdk1) and cyclin B1. Following treatment with MBIC, survivin co-immunoprecipitated with caspases with higher affinity in MDA-MB-231 compared to MCF-7 cells. Furthermore, silencing survivin caused a 4.5-fold increase in sensitivity of MDA-MB-231 cells to MBIC (IC50 = 4.4 ± 0.3). In addition, 4 weeks of MBIC administration in MDA-MB-231 cells inoculated BALB/c nude mice resulted in 79.7% reduction of tumor volume compared to the untreated group with no severe sign of toxicity. Our results demonstrated MBIC has multiple anti-tumor actions and could be a potential drug in breast cancer therapy.
Matched MeSH terms: Breast Neoplasms/drug therapy*
Anti-idiotype (Id) vaccine therapy has been tested and shown to be effective, in several animal models, for triggering the immune system to induce specific and protective immunity against bacterial, viral and parasitic infections. The administration of anti-Id antibodies as surrogate tumor-associated antigens (TAA) also represents another potential application of the concept of the Id network. Limited experience in human trials using anti-Id to stimulate immunity against tumors has shown promising results. In this "counter-point" article, we discuss our own findings showing the potential of anti-Id antibody vaccines to be novel therapeutic approaches to various human cancers and also discuss where anti-Id vaccines may perform better than traditional multiple-epitope antigen vaccines.
We aimed to investigate the relationship between genetic and environmental exposure and vitamin D status at age one, stratified by ethnicity. This study included 563 12-month-old infants in the HealthNuts population-based study. DNA from participants' blood samples was genotyped using Sequenom MassARRAY MALDI-TOF system on 28 single nucleotide polymorphisms (SNPs) in six genes. Using logistic regression, we examined associations between environmental exposure and SNPs in vitamin D pathway and filaggrin genes and vitamin D insufficiency (VDI). VDI, defined as serum 25-hydroxyvitamin D3(25(OH)D3) level ≤50nmol/L, was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infants were stratified by ethnicity determined by parent's country of birth. Infants formula fed at 12 months were associated with reduced odds of VDI compared to infants with no current formula use at 12 months. This association differed by ethnicity (Pinteraction=0.01). The odds ratio (OR) of VDI was 0.29 for Caucasian infants (95% CI, 0.18-0.47) and 0.04 for Asian infants (95% CI, 0.006-0.23). Maternal vitamin D supplementation during pregnancy and/or breastfeeding were associated with increased odds of infants being VDI (OR, 2.39; 95% CI, 1.11-5.18 and OR, 2.5; 95% CI, 1.20-5.24 respectively). Presence of a minor allele for any GC SNP (rs17467825, rs1155563, rs2282679, rs3755967, rs4588, rs7041) was associated with increased odds of VDI. Caucasian infants homozygous (AA) for rs4588 had an OR of 2.49 of being associated with VDI (95% CI, 1.19-5.18). In a country without routine infant vitamin D supplementation or food chain fortification, formula use is strongly associated with a reduced risk of VDI regardless of ethnicity. There was borderline significance for an association between filaggrin mutations and VDI. However, polymorphisms in vitamin D pathway related genes were associated with increased likelihood of being VDI in infancy.
Kuala Lumpur is the capital city of Malaysia with an estimated population of 1.55 million. Approximately 12% of the population live in squatter settlements occupying about 7% of the city total area. The squatter settlements generally are provided with basic amenities such as piped water, toilet facilities and electricity. Health indicators for the overall population of Kuala Lumpur are better off than for the rest of the country; however, intra-city differentials prevail along ethnic and socio-economic lines. Malays and Indians have higher rates for stillbirths, and neonatal, infant and toddler mortality than the Chinese. The wide disparity in the socio-economic status between the advantaged and the poor groups in the city is reflected in the dietary practices and nutritional status of young children from these communities. The percentage of preschool children from urban poor households with inadequate intakes of calories and nutrients is two to three times higher than those from the advantaged group. Compared to rural infants, a lower percentage of urban infants are breastfed. A lower percentage of Malays from the urban advantaged group breastfed, compared with the urban poor group. The reversed trend is found for the Chinese community. Growth attainment of young children from the urban poor is worse than the urban advantaged, though better than the rural poor. Health and nutritional practices implications related to both undernutrition and overnutrition are discussed, to illustrate the twin challenges of malnutrition in the city.
Malaysia is a rapidly developing country with a very young population, about 36% of which are below the age of 15 years. The standard of child health has improved greatly. However, there are great changes in the morbidity and mortality patterns of childhood diseases relating mainly to an improved standard of living; availability of safe water supply and adequate sanitary latrines; a higher literacy rate; rapid industrialisation and urban migration. The infant mortality rate has droppedfrom 50.1 per 1,000 livebirths in 1986 to 10.4 in 1995, and similar trends apply also to neonatal, perinatal and toddler mortality rates. Nevertheless, current major child health problems are those relating to events in the perinatal period and to infections. Despite improvements in the standard of neonatal care with the use ofhigh technology, the commonest cause of certified deaths still occur in the neonatal period. A rapid and inexpensive screening test for G6PD deficiency, a disease present in 2-3% of the population, is now widely available and, together with the use of phototherapy is largely responsible for the declining incidence of kernicterus in the country. Infections remain an important cause of morbidity and mortality although their patterns have changed. The very high (>95%) WHO-EPI-vaccines coverage rate is linked to the great reduction in the incidence of diphtheria, pertussis, tetanus, poliomyelitis and measles. Childhood tuberculosis is less common now, with about 250 - 300 reported cases per year and TB meningitis is rare with about 30-40 reported cases/year. The hepatitis B carrier rate is high (5%) and the introduction of routine newborn hepatitis B vaccination in 1989 is expected to have a positive impact as is the immunisation of young girls against rubella introduced in 1985 in reducing the incidence of congenital rubella syndrome. The incidence of malaria has declined but remains prevalent in the interiors of PeninsularMalaysia and in Sabah and Sarawak. Filariasis is largely under control. Unfortunately, despite great efforts at mosquito control, dengue virus infection remains a major problem with thousands of cases reported every year. Children are most susceptible to dengue haemorrhagic fever with many dying from the shock syndrome. The incidence of acute gastroenteritis has also dropped with most cases being due to a viral aetiology. Acute respiratory infections, mostly viral in origin, account for most attendances at paediatric outpatient services. Although staphylococcal and streptococcal impetigo and pneumonia are common, the incidence of streptococcal related diseases like rheumatic fever and acute glomendonephritis is rapidly declining. The nutritional status of children has improved in tandem with the rise in the standard of living, but subclinical malnutrition is prevalent, particularly among urban squatters and the rural poor. There is a disturbing decline in breastfeeding among urban working mothers. Poor weaning practices and food habits are responsible for the common occurrence of nutritional anaemia (5%) among infants and young children. Greater prosperity, rapid industrialisation and urbanisation have resulted in changes in the childhood disease pattern where non-communicable diseases assume greater importance as the problems of malnutrition and infection are gradually overcome. Road traffic accidents are a major killer and home accidents, largely preventable, are an important cause of morbidity and mortality. Childhood cancer, with about 550 new cases a year, is an important cause of death beyond infancy. Major congenital malformations, with a 1% prevalence rate, cause much ill-health. Thalassaemia is a particularly common genetic disease with fl thalassaemia gene frequency of about 5%. The prevalence of asthma is increasing, with a rate of 13.9% in the Kiang Valley but the prevalence of asthma-related symptoms is much higher. Physical, sexual child abuse and neglect, abandoned babies, substance abuse are but signs of stress of modern city living and peoples inability to cope with it. Although the general standard of child health has greatly improved, there are several states where it is still not satisfactory. In Sabah where there is a large illegal immigrant population, the infant mortality and infection rates are relatively high. In Kelantan and Trengganu, it is common for parents to refuse permission for a lumbar puncture required to treat meningitis. Other still deeply entrenched, culturally-related adverse health practices include : a fatalistic attitude to illness; a preference for traditional practitioners of medicine resulting in late treatment; and 'doctor-hopping' with unrealistic expectations of 'instant cure'. Childhood illnesses that are uncommon in Malaysia include: cystic fibrosis, coeliac disease, ulcerative colitis, Crohns disease, Sudden Infant Death Syndrome, Encopresis, enuresis and epiglottitis due to Haemophilus Influen:ae.