Dona Sinha

Chemopreventive and Chemotherapeutic Potential of Curcumin in Breast Cancer

Breast cancer remains the leading cause of cancer death among females worldwide. It signifies a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Current treatment modalities, including surgery, radiotherapy, and adjuvant chemotherapy or hormone therapy, have not been successful enough to impart significant improvement in the morbidity or mortality of breast cancer. This cancer is highly resistant to chemotherapy as no effective treatment exists for advanced disease conditions. Moreover, there is a dearth of ideal protein biomarkers of breast cancer in plasma or serum that can be used with desired sensitivity and specificity. Along with the existing therapeutic modalities of breast cancer the focus of researchers and clinicians have shifted towards the exploration of the preventive and therapeutic uses of natural products, including dietary phytoconstituents. Curcumin, the principal active component of Indian curry spice turmeric, has been found to exert preventive and therapeutic effects in various cancers. This is, in part, due to its ability to influence a diverse range of molecular targets and signaling pathways. The ability of curcumin to enhance the efficacy of existing chemotherapeutic agents is an added advantage. The current review critically analyzes various aspects of curcumin-related research conducted for molecular understanding of its efficacy in in vitro and in vivo models of breast cancer. The article also highlights recent developments with synthetic analogs of curcumin and nanocurcumin which are in the horizon of next generation targeted therapy with curcumin in breast cancer.

Curcumin protects DNA damage in a chronically arsenic-exposed population of West Bengal.

Groundwater arsenic contamination has been a health hazard for West Bengal, India. Oxidative stress to DNA is recognized as an underlying mechanism of arsenic carcinogenicity. A phytochemical, curcumin, from turmeric appears to be potent antioxidant and antimutagenic agent. DNA damage prevention with curcumin could be an effective strategy to combat arsenic toxicity. This field trial in Chakdah block of West Bengal evaluated the role of curcumin against the genotoxic effects of arsenic. DNA damage in human lymphocytes was assessed by comet assay and fluorescence-activated DNA unwinding assay. Curcumin was analyzed in blood by high performance liquid chromatography (HPLC). Arsenic induced oxidative stress and elucidation of the antagonistic role of curcumin was done by observation on reactive oxygen species (ROS) generation, lipid peroxidation and protein carbonyl. Antioxidant enzymes like catalase, superoxide dismutase, glutathione reductase, glutathioneS-transferase, glutathione peroxidase and non-enzymatic glutathione were also analyzed. The blood samples of the endemic regions showed severe DNA damage with increased levels of ROS and lipid peroxidation. The antioxidants were found with depleted activity. Three months curcumin intervention reduced the DNA damage, retarded ROS generation and lipid peroxidation and raised the level of antioxidant activity. Thus curcumin may have some protective role against the DNA damage caused by arsenic.

Antioxidant potential of tea reduces arsenite induced oxidative stress in Swiss albino mice

Environmental arsenic (As) is a potent human carcinogen and groundwater As contamination is a major health concern in West Bengal, India. Oxidative stress has been one of the prime factors in As-induced carcinogenicity. Generation of reactive oxygen species (ROS), beyond the bodys endogenous antioxidant balance cause a severe imbalance of the cellular antioxidant defence mechanism. Tea, a popular beverage has excellent chemopreventive and antioxidant properties. In this study it was investigated whether these flavonoids could ameliorate the arsenite (As III) induced oxidative stress in Swiss albino mice. Bio-monitoring with comet assay elicited that the increase in genotoxicity caused by As III was counteracted by both black tea and green tea. Elevated levels of lipid peroxides and protein carbonyl by As III were effectively reduced with green as well as black tea. They also exhibited protective action against the As III induced depletion of antioxidants like catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST) and glutathione (GSH) in mice liver tissue. Thus the tea polyphenols by virtue of their antioxidant potential may be used as an effective agent to reduce the As III induced oxidative stress in Swiss albino mice.

Nrf2-mediated redox signaling in arsenic carcinogenesis: a review

Arsenic is a ubiquitous toxic metalloid whose natural leaching from geogenic resources of earths crust into groundwater has become a dreadful health hazard to millions of people across the globe. Arsenic has been documented as a top most potent human carcinogen by Agency of Toxic Substances and Disease Registry. There have been a number of schools of opinions regarding the underlying mechanism of arsenic-induced carcinogenicity, but the theory of oxidative stress generated by arsenic has gained much importance. Imbalance in the cellular redox state and its associated complications have been closely associated with nuclear factor-erythroid 2-related factor 2 (Nrf2), a basic-leucine zipper transcription factor that activates the antioxidant responsive element and electrophilic responsive element, thereby upregulating the expression of a variety of downstream genes. This review has been framed on the lines of differential molecular responses of Nrf2 on arsenic exposure as well as the chemopreventive strategy which may be improvised to regulate Nrf2 in order to combat arsenic-induced oxidative stress and its long-term carcinogenic effect.

Curcumin prevents DNA damage and enhances the repair potential in a chronically arsenic-exposed human population in West Bengal, India.

Induction of oxidative stress and inhibition of DNA repair are possible modes of arsenic-induced carcinogenesis. In West Bengal, India, several districts contain high levels of arsenic, which are far above the WHO-recommended standard. Prevention of arsenic-induced oxidative stress and induction of repair enzymes by curcumin, an active ingredient of turmeric, may be an effective strategy to combat the adverse effects of arsenic. This study aimed at observing the role of curcumin in reducing 8-hydroxy-2′-deoxyguanosine formation and enhancing DNA repair capacity in the arsenic-exposed population of West Bengal. Chronically arsenic-exposed volunteers (n=66), who were asymptomatic, were selected for this study. Our results indicated that curcumin suppressed the 8-hydroxy-2′-deoxyguanosine level and OGG1 expression, which were increased by arsenic. Curcumin also induced DNA repair enzymes involved in the both base excision repair and nonhomologous end-joining pathways. In this study, both the protein expression and genetic profile were observed for poly-ADP-ribose polymerase 1, DNA &bgr; polymerase, X ray repair cross complement 1, DNA ligase III, DNA protein kinase catalytic sub-unit, X ray repair cross complement 4, DNA ligase IV, and topoisomerase II &bgr;. The results indicated that arsenic-inhibited DNA repair was induced by curcumin, both at protein and genetic levels. Thus, curcumin intervention may be a useful modality for the prevention of arsenic-induced carcinogenesis.

Platelet hyperactivity, neurobehavioral symptoms and depression among Indian women chronically exposed to low level of arsenic

The prevalence of neurobehavioral symptoms (NBS) and depression has been investigated in premenopausal rural women of West Bengal, India enrolled from arsenic (As) endemic (groundwater As 11-50 μg/L; n = 342) and control areas (As level ≤ 10 μg/L; n = 312). The subjective symptoms questionnaire and Becks 21-point depression inventory-II were used for the detection of NBS and depression, respectively. Platelet P-selectin expression was measured by flow cytometry, plasma neurotransmitter activity with high performance liquid chromatography and groundwater As level by atomic absorption spectroscopy. The As level in groundwater was 2.72 ± 1.18 μg/L in control and 28.3 ± 13.51 μg/L in endemic areas (p < 0.0001). Women residing in endemic areas demonstrated a higher prevalence of depressive symptoms (39.8 vs. 19.9%, p < 0.001) and anxiety (43.3 vs. 18.0% in control, p < 0.001), fatigue (68.4 vs. 23.4%, p < 0.0001), reduced sense of taste (15.8 vs. 4.5%, p<0.0001) and smell (14.9 vs. 5.8%, p < 0.001); burning sensation (36.8 vs. 5.4%, p < 0.0001) and tingling or numbness in the extremities (25.1 vs. 5.1%, p < 0.0001); and transient loss of memory (69.9 vs. 28.2%, p < 0.001). As-exposed women had 1.6-times more plasma epinephrine and norepinephrine (p < 0.05), 1.8-times higher level plasma serotonin with 28.9% lower intraplatelet serotonin (p < 0.05 for both), but their plasma dopamine level was not significantly different (p>0.05) from that of controls. Moreover, women from endemic areas had 2.3-times more P-selectin-expressing platelets in their circulation (p < 0.001). After controlling the potential confounders, chronic low level As (11-50 μg/L) exposure showed a positive association with the prevalence of neurobehavioral symptoms and depression among Indian women in their child-bearing age.

Chronic Low Level Arsenic Exposure Inflicts Pulmonary and Systemic Inflammation

Objective: To examine whether chronic low level arsenic (As) exposure (11-50 µg/L) from drinking water elicits inflammation and oxidative stress. Methods: Never-smoking pre-menopausal women (n=267) from Nadia district, West Bengal, India, were enrolled into two groups (i) control (n=122, median age 39 yr) from villages with <10 µg/L of As in groundwater, and (ii) exposed (n=145, median age 38 yr) from the same district where the groundwater As was 11-50 µg/L. As in water was measured by atomic absorption spectrophtometry with vapour generation assembly. Sputum cytology and hematology were done by standard procedures. Enzyme-linked immunosorbent assays were used to measure tumor necrosis factor-alpha (TNF-α), interleukin-6, 8, 10, 12 (IL-6, IL-8, IL-10, IL-12) and C-reactive protein (CRP) in plasma and cortisol in serum. Serum nitric oxide (NO) was measured colorimetrically, myleperoxidase (MPO) and neutrophil elastase by spectrophotometry, reactive oxygen species (ROS) by flow cytometry, and inducible nitric oxide synthase (iNOS) by immunocytochemistry. Results: As level in groundwater was higher in endemic areas (28.32 ± 13.51 vs. 2.72 ± 1.18, p<0.05), and exposed women had lower hemoglobin, leukocyte and erythrocyte levels but elevated platelet count than control and their sputum contained increased number of alveolar macrophages and inflammatory cells. In addition, they had elevated levels of TNF-α, IL-8, IL-6, IL-12, CRP, cortisol and NO but depleted level of IL-10 with excess generation of ROS and increased expression of iNOS in the airways. Neutrophils of As-exposed subjects had elevated levels of MPO and elastase. After controlling education and family income as potential confounders, the rise in pro-inflammatory mediators in blood and excess generation of ROS in the airways were positively associated with As levels in ground water. Conclusion: Drinking of water contaminated with low level of As for long causes pulmonary and systemic inflammation and generates excess ROS in the airways.

Tea phytochemicals for breast cancer prevention and intervention: From bench to bedside and beyond

The National Cancer Institute of the United States had projected breast cancer as one of the topmost prevalent malignancies of 2016. It was estimated that in 2016, 246,660 new cases of invasive breast cancer were expected to be diagnosed in women in the US, along with 61,000 new cases of non-invasive (in situ) breast cancer. The heterogeneity of breast cancer accounts for its differential molecular subtyping. Recent incorporation of high throughput approaches helps early prognosis of breast cancer, but recurrence of the disease stands to be one of the most daunting fact behind non-availability of third line treatment. At this point of crisis, application of chemopreventive measures could possibly resolve the enigma of breast cancer. The world class beverage tea has proven its efficacy in ameliorating various genetic and epigenetic anomalies in breast cancer. Tea phytoconstituents are known to modulate myriad molecular events which include prominent regulators of intracellular signaling, such as phosphatidylinositide 3-kinase/protein kinase B/nuclear factor-κB, epidermal growth factor receptor, vascular endothelial growth factor, B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein in the development and progression of breast carcinoma. This review aims to encompass the detailed modulatory roles of tea phytochemicals, their analogs and nanoformulations against mammary carcinoma and the probability of using tea in therapeutic management of breast cancer. Finally, current limitations, challenges and future directions of tea and breast cancer research are also critically discussed.

Health Effects of Indoor Air Pollution Due to Cooking with Biomass Fuel

Indoor air pollution (IAP) due to daily household cooking with unprocessed solid biomass such as wood, dung and crop residues is a serious health hazard in the poor, developing countries of Asia, sub-Saharan Africa and Latin America. Globally, 2.8 billion people use biomass for domestic energy. Incomplete combustion of biomass emits smoke that contains a host of potentially health-damaging particulate and gaseous pollutants, some of which like benzo(a)pyrene, 1,3-butadiene and benzene are known human carcinogens. IAP from biomass burning is responsible for excess mortality and morbidity. An estimated four million deaths, mostly from cardio-pulmonary causes, have been attributed to biomass use. Children, women and the elderly people are most vulnerable. Chronic inhalation of biomass smoke induces lung function decrement, increases the risk of life-threatening chronic obstructive pulmonary disease, evokes pulmonary and systemic inflammation and consequent oxidative stress, and contributes to the development of hypertension and cardio-vascular diseases. Daily household cooking with biomass was associated with higher incidences of anemia, platelet hyperactivity, and altered number and activities of the immune cells. Oxidative stress generated by biomass smoke mediates chromosomal and DNA damage and impairment in DNA repair mechanism in the exposed cells. In addition, chronic inhalation of biomass smoke up-regulates protein kinase B/Akt signaling and metaplasia and dysplasia of airway cells, implying increased risk of lung cancer. Women who cooked with biomass also had altered serotonergic activity with greater prevalence of depression. Thus, IAP due to household cooking with biomass adversely affects both physical and mental health of the people.

Epigallocatechin-3-gallate partially restored redox homeostasis in arsenite-stressed keratinocytes: EGCG MODULATED REDOX HOMEOSTASIS IN ARSENITE-STRESSED KERATINOCYTES

Arsenite (AsIII) is known for inducing severe oxidative stress and skin carcinogenesis. Contrastingly, phytochemical, epigallocatechin‐3‐gallate (EGCG) combats toxic insults. Our study focused on the effect of EGCG on redox status of AsIII‐stressed normal human keratinocytes, HaCaT cells. EGCG (50 μm) increased the cell viability by 29% in AsIII (50 μm) insulted HaCaT cells but exhibited pro‐oxidant activity by elevated expression of the oxidative stress markers. EGCG was effective not only in reducing AsIII‐induced nuclear expression of Nrf2 and Nrf2Ser40 but also in increasing nuclear expression of Keap1 both at protein and mRNA level. EGCG did not have similar effects on all Nrf2 downstream targets. EGCG elevated expression of HO‐1 and γ‐GCL,showed no change in MRP1 but decreased superoxide dismutase, NAD(P)H dehydrogenase quinone 1 and glutathione S transferase activity in AsIII‐treated HaCaT cells. EGCG along with AsIII caused decreased phosphorylation of Nrf2 at ser40 residue, which might have facilitated Keap1‐mediated nuclear export and degradation of Nrf2 and paved the pro‐survival signal for AsIII‐insulted HaCaT cells. In conclusion, it might be indicated that EGCG in spite of inducing the pro‐oxidant effect was effective in increasing the viability of AsIII‐treated HaCaT cells by partially restoring the Nrf2/Keap1‐mediated signaling axis.