Mohammad Fahad Ullah

SOY ISOFLAVONE GENISTEIN INDUCES CELL DEATH IN BREAST CANCER CELLS THROUGH MOBILIZATION OF ENDOGENOUS COPPER IONS AND GENERATION OF REACTIVE OXYGEN SPECIES

SCOPE Worldwide geographical variation in cancer incidence indicates a correlation between dietary habits and cancer risk. Epidemiological studies have suggested that populations with high isoflavone intake through soy consumption have lower rates of breast, prostate, and colon cancer. Isoflavone genistein in soybean is considered a potent chemopreventive agent against cancer. Although several mechanisms have been proposed, a clear anticancer action mechanism of genistein is still not known. METHODS AND RESULTS Here, we show that the cytotoxic action of genistein against breast cancer cells involves mobilization of endogenous copper. Further, whereas the copper specific chelator neocuproine is able to inhibit the apoptotic potential of genistein, the molecules which specifically bind iron (desferroxamine mesylate) and zinc (histidine) are relatively ineffective in causing such inhibition. Also, genistein-induced apoptosis in these cells is inhibited by scavengers of reactive oxygen species (ROS) implicating ROS as effector elements leading to cell death. CONCLUSIONS As copper levels are known to be considerably elevated in almost all types of cancers, in this proof-of-concept study we show that genistein is able to target endogenous copper leading to prooxidant signaling and consequent cell death. We believe that such a mechanism explains the anticancer effect of genistein as also its preferential cytotoxicity towards cancer cells.

Redox cycling of endogenous copper by thymoquinone leads to ROS-mediated DNA breakage and consequent cell death: putative anticancer mechanism of antioxidants

Plant-derived dietary antioxidants have attracted considerable interest in recent past for their chemopreventive and cancer therapeutic abilities in animal models. Thymoquinone (TQ) is the major bioactive constituent of volatile oil of Nigella sativa and has been shown to exert various pharmacological properties, such as anti-inflammatory, cardiovascular, analgesic, anti-neoplastic, anticancer and chemopreventive. Although several mechanisms have been suggested for the chemopreventive and anticancer activity of TQ, a clear mechanism of action of TQ has not been elucidated. TQ is a known antioxidant at lower concentrations and most of the studies elucidating the mechanism have centered on the antioxidant property. However, recent publications have shown that TQ may act as a prooxidant at higher concentrations. It is well known that plant-derived antioxidants can switch to prooxidants even at low concentrations in the presence of transition metal ions such as copper. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Copper is an important metal ion present in the chromatin and is closely associated with DNA bases, particularly guanine. Using human peripheral lymphocytes and comet assay, we first show that TQ is able to cause oxidative cellular DNA breakage. Such a DNA breakage can be inhibited by copper-chelating agents, neocuproine and bathocuproine, and scavengers of reactive oxygen species. Further, it is seen that TQ targets cellular copper in prostate cancer cell lines leading to a prooxidant cell death. We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of plant-derived antioxidants.

Pharmacological Intervention through Dietary Nutraceuticals in Gastrointestinal Neoplasia

Neoplastic conditions associated with gastrointestinal (GI) tract are common worldwide with colorectal cancer alone accounting for the third leading rate of cancer incidence. Other GI malignancies such as esophageal carcinoma have shown an increasing trend in the last few years. The poor survival statistics of these fatal cancer diseases highlight the need for multiple alternative treatment options along with effective prophylactic strategies. Worldwide geographical variation in cancer incidence indicates a correlation between dietary habits and cancer risk. Epidemiological studies have suggested that populations with high intake of certain dietary agents in their regular meals have lower cancer rates. Thus, an impressive embodiment of evidence supports the concept that dietary factors are key modulators of cancer including those of GI origin. Preclinical studies on animal models of carcinogenesis have reflected the pharmacological significance of certain dietary agents called as nutraceuticals in the chemoprevention of GI neoplasia. These include stilbenes (from red grapes and red wine), isoflavones (from soy), carotenoids (from tomatoes), curcuminoids (from spice turmeric), catechins (from green tea), and various other small plant metabolites (from fruits, vegetables, and cereals). Pleiotropic action mechanisms have been reported for these diet-derived chemopreventive agents to retard, block, or reverse carcinogenesis. This review presents a prophylactic approach to primary prevention of GI cancers by highlighting the translational potential of plant-derived nutraceuticals from epidemiological, laboratory, and clinical studies, for the better management of these cancers through consumption of nutraceutical rich diets and their intervention in cancer therapeutics.

Sulforaphane (SFN): An Isothiocyanate in a Cancer Chemoprevention Paradigm

The International Agency for Research on Cancer (IARC) in its latest World Cancer Report (2014) has projected the increase in the global cancer burden from 14 million (2012) to 22 million incidence annually within the next two decades. Such statistics warrant a collaborative engagement of conventional and complementary and alternative therapies to contain and manage cancer. In recent years, there has been a shift in the cancer chemoprevention paradigm with a significant focus turning towards bioactive components of human diets for their anticancer properties. Since diet is an integral part of lifestyle and given that an estimated one third of human cancers are believed to be preventable though appropriate lifestyle modification including dietary habits, the current shift in the conventional paradigm assumes significance. Several epidemiological studies have indicated that consumption of broccoli is associated with a lower risk of cancer incidence including breast, prostate, lung, stomach and colon cancer. The edible plant belonging to the family of cruciferae such as broccoli is a rich source of glucoraphanin, a precursor of isothiocyanate sulforaphane which is considered to be a potent anti-cancer agent. Plant-based dietary agents such as sulforaphane mimic chemotherapeutic drugs such as vorinostat, possessing histone deacetylase inhibition activity. Evidence from epidemiological and experimental studies have emerged, enhancing the clinical plausibility and translational value of sulforaphane in cancer chemoprevention. The present review provides the current understanding of the cancer chemopreventive pharmacology of sulforaphane towards its potential as an anticancer agent.

Mobilization of Intracellular Copper by Gossypol and Apogossypolone Leads to Reactive Oxygen Species-Mediated Cell Death: Putative Anticancer Mechanism

There is compelling evidence that serum, tissue and intracellular levels of copper are elevated in all types of cancer. Copper has been suggested as an important co-factor for angiogenesis. It is also a major metal ion present inside the nucleus, bound to DNA bases, particularly guanine. We have earlier proposed that the interaction of phenolic-antioxidants with intracellular copper leads to the generation of reactive oxygen species (ROS) that ultimately serve as DNA cleaving agents. To further validate our hypothesis we show here that the antioxidant gossypol and its semi-synthetic derivative apogossypolone induce copper-mediated apoptosis in breast MDA-MB-231, prostate PC3 and pancreatic BxPC-3 cancer cells, through the generation of ROS. MCF10A breast epithelial cells refractory to the cytotoxic property of these compounds become sensitized to treatment against gossypol, as well as apogossypolone, when pre-incubated with copper. Our present results confirm our earlier findings and strengthen our hypothesis that plant-derived antioxidants mobilize intracellular copper instigating ROS-mediated cellular DNA breakage. As cancer cells exist under significant oxidative stress, this increase in ROS-stress to cytotoxic levels could be a successful anticancer approach.

Antioxidative and xanthine oxidase inhibitory activities and phytochemical screening of the hydro-alcoholic extract of mace, aril of Myristica fragrans: Implication as an adjuvant therapy in gout

ABSTRACT Myristica fragrans derivatives are used as spices in cuisines and also serve as an important source of traditional medicine worldwide. The present study has evaluated the antioxidative potential of the hydro-methanolic extract of the fruit aril of M. fragrans, which is also referred to as mace. This study also includes a quantitative phytochemical assessment of the extract and focuses on the ability of the extract to inhibit xanthine oxidase, a molecular target involved in nucleic acid metabolism and the enzyme responsible for the development of gout disease. The extract was found to contain different classes of secondary metabolites, including flavonoids, phenolics, tannins, alkaloids, and saponins. Furthermore, the antioxidative potential of the extract was evaluated against the radicals 2,2-azino-bis(3-ethylbenzothiazoline- 6-sulfonic acid) diammonium salt and 2,2-diphenyl-1-pycrylhydrazyl, and there was a progressive reduction of the radicals with increasing doses of the extract. Moreover, a ferric reducing power assay also showed the antioxidant activity of the crude extract as compared to ascorbic acid, a well-known antioxidant. Another significant finding of the study is that the mace extract also considerably inhibits the enzyme xanthine oxidase in a concentration-dependent manner. Our results partially support the use of mace in dietary regimens as a nutraceutical that could serve as a prophylactic strategy or an adjuvant for the prevention and therapy of gout disease.

Critical Dietary Factors in Cancer Chemoprevention

Critical dietary factors in cancer chemoprevention / , Critical dietary factors in cancer chemoprevention / , کتابخانه دیجیتال جندی شاپور اهواز

Dietary Factors May Influence the Clinical Outcome of Chemotherapy in Cancer Multidrug Resistance

A substantive burden of cancer mortality results from poor prognosis of the disease due to the failure of chemotherapeutic regimen under the influence of Multidrug Resistance (MDR). The outcome of chemotherapy which is the most effective treatment for patients with cancer is impeded by the development of drug resistance. Anticancer drugs can fail to kill cancer cells for various reasons that include variations in the absorption, metabolism, and delivery of drug to target tissues and tumor location in parts of the body into which the drugs do not easily penetrate. In addition, certain cancer cells develop resistance by micro-evolutionary means through mutations occurring in the drug target, thus rendering the drugs ineffective. However, the most common of these mechanisms is the efflux of hydrophobic drugs mediated by energy driven ATP-binding cassette (ABC) family of transporters such as P-glycoprotein (P-gp), an integral membrane protein over-expressed in several malignancies. Various generations of MDR modulators have presented novel and improved interventions, though not to the perfection. Studies have shown that natural compounds found in vegetables, fruits, plant-derived beverages, and herbal dietary supplements not only have anticancer properties but may also modulate P-gp activity. P-gp inhibitors found in natural products, especially those found in plants of dietary origin and traditional medicine, have the potential to be developed as MDR reversing agents as adjuvant to chemotherapy leading to better clinical prognosis.