Bharti Odhav

Natural products for cancer prevention: a global perspective

The control of cancer, the second leading cause of death worldwide, may benefit from the potential that resides in alternative therapies. The primary carcinogens stem from a variety of agricultural, industrial, and dietary factors. Conventional therapies cause serious side effects and, at best, merely extend the patients lifespan by a few years. There is thus the need to utilise alternative concepts or approaches to the prevention of cancer. This review focuses on the many natural products that have been implicated in cancer prevention and that promote human health without recognisable side effects. These molecules originate from vegetables, fruits, plant extracts, and herbs.

Review on Natural Coumarin Lead Compounds for Their Pharmacological Activity

Coumarin (2H-1-benzopyran-2-one) is a plant-derived natural product known for its pharmacological properties such as anti-inflammatory, anticoagulant, antibacterial, antifungal, antiviral, anticancer, antihypertensive, antitubercular, anticonvulsant, antiadipogenic, antihyperglycemic, antioxidant, and neuroprotective properties. Dietary exposure to benzopyrones is significant as these compounds are found in vegetables, fruits, seeds, nuts, coffee, tea, and wine. In view of the established low toxicity, relative cheapness, presence in the diet, and occurrence in various herbal remedies of coumarins, it appears prudent to evaluate their properties and applications further.

Immune responses in cancer

The complex of humoral factors and immune cells comprises two interleaved systems, innate and acquired. Immune cells scan the occurrence of any molecule that it considers to be nonself. Transformed cells acquire antigenicity that is recognized as nonself. A specific immune response is generated that results in the proliferation of antigen-specific lymphocytes. Immunity is acquired when antibodies and T-cell receptors are expressed and up-regulated through the formation and release of lymphokines, chemokines, and cytokines. Both innate and acquired immune systems interact to initiate antigenic responses against carcinomas. A new approach to the treatment of cancer has been immunotherapy, which aims to up-regulate the immune system in order that it may better control carcinogenesis. Currently, several forms of immunotherapy that use natural biological substances to activate the immune system are being explored therapeutically. The various forms of immunotherapy fall into three main categories: monoclonal antibodies, immune response modifiers, and vaccines. While these modalities have individually shown some promise, it is likely that the best strategy to combat cancer may require multiple immunotherapeutic strategies in order to demonstrate benefit in different patient populations. It may be that the best results are obtained with vaccines in combination with a variety of immunotherapy combinations. Another potent strategy may be in combining with more traditional cancer drugs as evidenced from the benefit derived from enhancing the efficacy of chemotherapy with cytokines. Through such concerted efforts, a durable, therapeutic antitumour immune response may be achieved and maintained over the course of a patients lifespan.

Aflatoxin B1-induced toxicity in HepG2 cells inhibited by carotenoids: morphology, apoptosis and DNA damage

Abstract Aflatoxin B1 (AFB1) is a fungal toxin that has been associated with primary hepatocellular carcinoma (HCC) in humans. This study was undertaken to determine the cellular and molecular mechanisms by which the antioxidants β-carotene and lycopene inhibit AFB1-induced toxic changes in human hepatocytes (HepG2 cells). An in vitro system was optimized to test the chemoprotective effects of lycopene and β-carotene on HepG2 cells exposed to different concentrations of AFB1. Ultrastructurally, HepG2 cells cultured in the presence of AFB1 showed mitochondrial damage, nuclear condensation and a loss of cell-to-cell contact; the latter was reflected in the observation of dysfunctional gap junctions, resulting in a loss of cell-to-cell communication. At the genomic level, AFB1 formed AFB1-N7-guanine adducts, caused apoptotic cell death and suppressed p53 protein expression. In the presence of the carotenoids, survival of cells exposed to AFB1 was increased, and there was also a significant increase in cellular mitochondrial activity. Our results demonstrate that HepG2 cells pretreated with lycopene and β-carotene are protected from the toxic effects of AFB1 at both the cellular and molecular levels.

Translocation and accumulation of Cr, Hg, As, Pb, Cu and Ni by Amaranthus dubius (Amaranthaceae) from contaminated sites.

Phytoremediation is an emerging technology where specially selected and engineered metal-accumulating plants are used for bioremediation. This study was undertaken to evaluate the potential of Amaranthus dubius for phytoremediation of chromium (Cr), mercury (Hg), arsenic (As), lead (Pb), copper (Cu) and nickel (Ni). Locally gathered soil and plants of A. dubius were investigated for the metals from a regularly cultivated area, a landfill site and a waste water treatment site. Metals were extracted from the samples using microwave-digestion and analyzed using Inductively Coupled Plasma–Mass Spectroscopy. The mode of phytoremediation, effect of the metals on the plants, ability of the plant to extract metals from soil (Bioconcentration Factor) and the ability of the plants to move the metals to the aerial parts of the plants (Translocation Factor) were evaluated. The survey of the three sites showed that soils were heavily contaminated with Cr, Hg, Cu and Ni. These levels were far above acceptable standards set for soils and above the standards set for the Recommended Dietary Allowance. Specimens of A. dubius from the three sites showed that they could tolerate Hg, sequester it from the soil, and translocate it to the shoots. Cr could only be removed from the soil and stored in the roots, with limited amounts translocated to the aerial parts. Pb, As, Ni, and Cu have some degree of transportability from the soil to the roots but not to aerial parts. The ability of A. dubius to be considered for phytoremediation has to be viewed with caution because translocation of the metals to the aerial parts of the plant is limited.

Synthesis and antimosquito properties of 2,6-substituted benzo[d]thiazole and 2,4-substituted benzo[d]thiazole analogues against Anopheles arabiensis.

A novel and efficient one pot synthesis was developed for 2,6-substituted-benzo[d]thiazole analogues 4a-k and 2,4-substituted-benzo[d]thiazole analogues 4l-pvia three component condensation reaction of substituted arylaldehyde, 2-amino-6-halo/4-methyl-benzo[d]thiazole and 2-naphthol or 6-hydroxyquinoline in presence of 10% w/v NaCl in water by microwave method. This method enabled for short reaction times, easy work-up and significant high yields. The title compound 4b was used for single crystal X-ray studies in order to understand its conformation and packing features. The title compounds 4a-p were screened for antimosquito properties such as repellency, insecticidal and larvicidal activity against Anopheles arabiensis by mosquito feeding-probing assay, cone bio-assay and standard WHO larvicidal assay, respectively. Among these analogous 4b, 4d and 4p exhibit the highest repellent activity comparable to the positive control DEET, and 4a and 4k knockdown most mosquitoes on repellent assays.

In vitro toxicity testing of zinc tetrasulfophthalocyanines in fibroblast and keratinocyte cells for the treatment of melanoma cancer by photodynamic therapy.

A series of water-soluble tetrasulfonated metallophthalocyanines (MPcs) dyes have been studied to be used as a drug or photosensitizer (PS) in photodynamic therapy (PDT) for the treatment of cancers. During PDT the PS is administrated intravenously or topically to the patient before laser light at an appropriate wavelength is applied to the cancerous area to activate the PS. The activated PS will react with oxygen typically present in the cancerous tissue to generate reactive oxygen species for the destruction of the cancerous tissue. This in vitro study aimed at investigating the cytotoxic effects of different concentrations of zinc tetrasulfophthalocyanines (ZnTSPc) activated with a diode laser (λ = 672 nm) on melanoma, keratinocyte and fibroblast cells. To perform this study 3 × 10⁴ cells/ml were seeded in 24-well plates and allowed to attach overnight, after which cells were treated with different concentrations of ZnTSPc. After 2h, cells were irradiated with a constant light dose of 4.5J/cm². Post-irradiated cells were incubated for 24 h before cell viability was measured using the CellTiter-Blue Viability Assay. Data indicated high concentrations of ZnTSPc (60-100 μg/ml) in its inactive state are cytotoxic to the melanoma cancer cells. Also, results showed that photoactivated ZnTSPc (50 μg/ml) was able to reduce the cell viability of melanoma, fibroblast and keratinocyte cells to 61%, 81% and 83% respectively. At this photosensitizing concentration the efficacy the treatment light dose of 4.5J/cm² against other light doses of 2.5J/cm², 7.5J/cm² and 10J/cm² on the different cell lines were analyzed. ZnTSPc at a concentration of 50 μg/ml activated with a light dose of 4.5J/cm² was the most efficient for the killing of melanoma cancer cells with reduced killing effects on healthy normal skin cells in comparison to the other treatment light doses. Melanoma cancer cells after PDT with a photosensitizing concentration of 50μg/ml and a treatment light dose of 4.5J/cm² showed certain apoptosis characteristics such as chromatin condensation and fragmentation of the nucleus. This concludes that low concentrations of ZnTSPc activated with the appropriate light dose can be used to induce cell death in melanoma cells with the occurrence of minimal damage to surrounding healthy tissue.

The effect of modified atmospheres and packaging on patulin production in apples.

This study was undertaken to determine the effectiveness of modified atmospheres and packaging materials on the growth of Penicillium expansum and patulin production in apples. Granny Smith apples were surface sterilized with 76% ethanol and inoculated with 0.1 ml of a 1.1 x 10(7) spore/ml P. expansum spore suspension. The apples were packaged either in polyethylene (PE) or polypropylene (PP) and treated with three different gas combinations, viz., 58% CO2/42% N2, 48% CO2/52% N2, and 88% CO2/12% N2, and were then incubated for 14 days at 25 degrees C. Fungal growth was monitored every 2 to 4 days by measuring radial growth from the point of inoculation. After the 14th day, apples were pulped, and patulin was extracted, purified, and quantified by high-performance liquid chromatography. PP did not inhibit fungal growth in any of the atmospheres tested, and it only inhibited patulin production in atmospheric gas and 58% CO2/42% N2. PE was very effective and inhibited fungal growth by four- or fivefold, depending on the modified atmosphere. Patulin production in PE-packaged apples was almost completely inhibited by all three gas combinations. Gas chromatographic analysis of the PE-packaged samples before and after the incubation period showed that CO2 levels dropped and N2 levels increased for all of the atmospheres tested. Our studies showed conclusively that PE is an excellent packaging material for the storage of apples since it inhibited the growth of P. expansum, thereby allowing <3.2 microg/ml of patulin to be produced, regardless of gaseous environment.

Modulating effects of fumonisin B1 and ochratoxin A on leukocytes and messenger cytokines of the human immune system

Fumonisin B1 and ochratoxin A are mycotoxins of importance to public health and agro-economics. Although much is known about their cellular toxicity and carcinogenesis in animals, there are no reports of adverse effects on immune cells (leukocytes) or on the immune modulation of the molecular messengers (cytokines) in humans. This study was designed, therefore, to determine and compare the morphological effects of fumonisin B1 and ochratoxin A on lymphocytes and neutrophils harvested from the circulation of healthy volunteer subjects and patients with oesophageal and breast carcinomas. Both fumonisin B1 and ochratoxin A reduced the number of viable lymphocytes and neutrophils harvested from the circulation of volunteer subjects carcinoma patients in a dose-dependent manner. Leukocyte secretion of cytokines on exposure to the mycotoxins was evaluated by immunocytochemical methods. Expression of granulocyte-colony stimulating factor (G-CSF), tumour necrosis factor (TNF-alpha) and chemokine (CX3CR1) receptors were determined on the circulating leukocytes and the immunolabelling visualized by brightfield-and electron-microscopy. Cytokine levels were determined in the circulation of healthy volunteer subjects and in patients with oesophageal and breast carcinomas since they reflect the status of the immune system in humans. The findings of this study on immunocytes (leukocytes) and the immune molecular messengers (cytokines) suggest that fumonisin B1 and ochratoxin A have an immuno-suppressive effect in humans, in particular patients with cancer by impairing immune surveillance.

Synthesis and Antitubercular Activity of 2-(substituted phenyl/benzyl-amino)-6-(4-chlorophenyl)-5-(methoxycarbonyl)-4-methyl-3,6-dihydropyrimidin-1-ium Chlorides

A series of 2‐(substituted phenyl/benzyl‐amino)‐6‐(4‐chlorophenyl)‐5‐(methoxycarbonyl)‐4‐methyl‐3,6‐dihydropyrimidin‐1‐ium chlorides 7–13 and 15 was synthesized in their hydrochloride salt form. The title compounds were characterized by FT‐IR, NMR (1H and 13C) and elemental analysis. They were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv, multidrug resistance tuberculosis and extensively drug resistance tuberculosis by agar diffusion method and tested for the cytotoxic action on peripheral blood mononuclear cells by MTT assay. Among all the tested compounds in the series, compounds 7 and 11 emerged as promising antitubercular agents at 16 μg/mL against multidrug resistance tuberculosis and over 64 μg/mL against extensively drug resistance tuberculosis. The conformational features and supramolecular assembly of the promising compounds 7 and 11 were determined by single crystal X‐ray study.