Solubility enhancement and targeted delivery of a potent anticancer flavonoid analogue to cancer cells using ligand decorated dendrimer nano-architectures.

Conventional chemotherapy using small molecule drugs is marred by several challenges such as short half-life, low therapeutic index and adverse systemic side effects. In this regard, targeted therapies using ligand directed polyamidoamine (PAMAM) dendrimers could be a promising strategy to specifically deliver anticancer drugs to cancer cells overexpressing complementary receptor binding domains. The aim of this study was to utilize folate decorated PAMAM to enhance the aqueous solubility of a highly hydrophobic but very potent anticancer flavonoid analogue, 3,4-difluorobenzylidene diferuloylmethane (CDF) and to deliver it specifically to folate receptor overexpressing cervical cancer cells (HeLa) and ovarian cancer cells (SKOV3). As compared to the non-targeted formulation, the targeted formulation exhibited significant anticancer activity with higher accumulation in folate receptor overexpressing cells, larger population of apoptotic cancer cells, elevated expression of tumor suppressor phosphatase and tensin homolog (PTEN), and inhibition of nuclear factor kappa B (NFκB) which further confirmed the targeting ability and the promising anticancer activity of the folate based nanoformulation.

The bounty of nature for changing the cancer landscape.

The landscape of cancer has changed considerably in past several years, due mainly to aggressive screening, accumulation of data from basic and epidemiological studies, and the advances in translational research. Natural anticancer agents have always been a part and parcel of cancer research. The initial focus on natural anticancer agents was in context of their cancer chemopreventive properties but their ability to selectively target oncogenic signaling pathways has also been recognized. In light of the rapid advancements in our understanding of the role of microRNAs, cancer stem cells, and epigenetic events in cancer initiation and progression, a number of natural anticancer agents are showing promise in vitro, in vivo as well as in preclinical studies. Moreover, parent structures of natural agents are being extensively modified with the hope of improving efficacy, specificity, and bioavailability. In this article, we focus on two natural agents, 3,3'-diindolylmethane and garcinol, along with 3,4-difluorobenzo curcumin, a synthetic analog of natural agent curcumin. We showcase how these anticancer agents are changing cancer landscape by modulating novel microRNAs, epigenetic factors, and cancer stem cell markers. These activities are relevant and being appreciated for overcoming drug resistance and inhibition of metastases, the two overarching clinical challenges in modern medicine.

Novel Holistic Approaches for Overcoming Therapy Resistance in Pancreatic and Colon Cancers.

Gastrointestinal (GI) cancers, such as of the colon and pancreas, are highly resistant to both standard and targeted therapeutics. Therapy-resistant and heterogeneous GI cancers harbor highly complex signaling networks (the resistome) that resist apoptotic programming. Commonly used gemcitabine or platinum-based regimens fail to induce meaningful (i.e. disease-reversing) perturbations in the resistome, resulting in high rates of treatment failure. The GI cancer resistance networks are, in part, due to interactions between parallel signaling and aberrantly expressed microRNAs (miRNAs) that collectively promote the development and survival of drug-resistant cancer stem cells with epithelial-to-mesenchymal transition (EMT) characteristics. The lack of understanding of the resistance networks associated with this subpopulation of cells as well as reductionist, single protein-/pathway-targeted approaches have made 'effective drug design' a difficult task. We propose that the successful design of novel therapeutic regimens to target drug-resistant GI tumors is only possible if network-based drug avenues and agents, in particular 'natural agents' with no known toxicity, are correctly identified. Natural agents (dietary agents or their synthetic derivatives) can individually alter miRNA profiles, suppress EMT pathways and eliminate cancer stem-like cells that derive from pancreatic cancer and colon cancer, by partially targeting multiple yet meaningful networks within the GI cancer resistome. However, the efficacy of these agents as combinations (e.g. consumed in the diet) against this resistome has never been studied. This short review article provides an overview of the different challenges involved in the understanding of the GI resistome, and how novel computational biology can help in the design of effective therapies to overcome resistance.

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.

The Role of Cancer Stem Cells in Recurrent and Drug-Resistant Lung Cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide with a 5-year overall survival rate of less than 20 %. Considering the treatments currently available, this statistics is shocking. A possible explanation for the disconnect between sophisticated treatments and the survival rate can be related to the post-treatment enrichment of Cancer Stem Cells (CSCs), which is one of a sub-set of drug resistant tumor cells with abilities of self-renewal, cancer initiation, and further maintenance of tumors. Lung CSCs have been associated with resistance to radiation and chemotherapeutic treatments. CSCs have also been implicated in tumor recurrence because CSCs are not typically killed after conventional therapy. Investigation of CSCs in determining their role in tumor recurrence and drug-resistance relied heavily on the use of specific markers present in CSCs, including CD133, ALDH, ABCG2, and Nanog. Yet another cell type that is also associated with increased resistance to treatment is epithelial-to-mesenchymal transition (EMT) phenotypic cells. Through the processes of EMT, epithelial cells lose their epithelial phenotype and gain mesenchymal properties, rendering EMT phenotypic cells acquire drug-resistance. In this chapter, we will further discuss the role of microRNAs (miRNAs) especially because miRNA-based therapies are becoming attractive target with respect to therapeutic resistance and CSCs. Finally, the potential role of the natural agents and synthetic derivatives of natural compounds with anti-cancer activity, e.g. curcumin, CDF, and BR-DIM is highlighted in overcoming therapeutic resistance, suggesting that the above mentioned agents could be important for better treatment of lung cancer in combination therapy.

Parenterally administrable nano-micelles of 3,4-difluorobenzylidene curcumin for treating pancreatic cancer.

Pancreatic cancer remains one of the most devastating diseases in terms of patient mortality rates for which current treatment options are very limited. 3,4-Difluorobenzylidene curcumin (CDF) is a nontoxic analog of curcumin (CMN) developed in our laboratory, which exhibits extended circulation half-life, while maintaining high anticancer activity and improved pancreas specific accumulation in vivo, compared with CMN. CDF however has poor aqueous solubility and its dose escalation for systemic administration remains challenging. We have engineered self-assembling nano-micelles of amphiphilic styrene-maleic acid copolymer (SMA) with CDF by non-covalent hydrophobic interactions. The SMA-CDF nano-micelles were characterized for size, charge, drug loading, release, serum stability, and in vitro anticancer activity. The SMA-CDF nano-micelles exhibited tunable CDF loading from 5 to 15% with excellent aqueous solubility, stability, favorable hemocompatibility and sustained drug release characteristics. The outcome of cytotoxicity testing of SMA-CDF nano-micelles on MiaPaCa-2 and AsPC-1 pancreatic cancer cell lines revealed pronounced antitumor response due to efficient intracellular trafficking of the drug loaded nano-micelles. Additionally, the nano-micelles are administrable via the systemic route for future in vivo studies and clinical translation. The currently developed SMA based nano-micelles thus portend to be a versatile carrier for dose escalation and targeted delivery of CDF, with enhanced therapeutic margin and safety.

Molecular targets of naturopathy in cancer research: bridge to modern medicine.

The relevance of naturopathy (defined as the practice of medicine for the treatment of human diseases with natural agents) in human cancer is beginning to be appreciated, as documented by renewed interest in nutraceutical research, the natural anticancer agents of dietary origin. Because of their pleiotropic effects and the ability to modulate multiple signaling pathways, which is a good attribute of natural agents, nutraceuticals have frequently been demonstrated to re-sensitize drug-resistant cancers. The effectiveness of nutraceuticals can be further enhanced if the tools for the relative assessment of their molecular targets are readily available. Such information can be critical for determining their most effective uses. Here, we discuss the anticancer potential of nutraceuticals and the associated challenges that have interfered with their translational potential as a naturopathic approach for the management of cancers. In the years to come, an efficient screening and assessment of molecular targets will be the key to make rapid progress in the area of drug design and discovery, especially focusing on evidence-based development of naturopathy for the treatment of human malignancies.

The Role of Nutraceuticals in Pancreatic Cancer Prevention and Therapy: Targeting Cellular Signaling, MicroRNAs, and Epigenome.

Pancreatic cancer is one of the most aggressive malignancies in US adults. Experimental studies have found that antioxidant nutrients could reduce oxidative DNA damage, suggesting that these antioxidants may protect against pancreatic carcinogenesis. Several epidemiologic studies showed that dietary intake of antioxidants was inversely associated with the risk for pancreatic cancer, demonstrating the inhibitory effects of antioxidants on pancreatic carcinogenesis. Moreover, nutraceuticals, the anticancer agents from diet or natural plants, have been found to inhibit the development and progression of pancreatic cancer through the regulation of cellular signaling pathways. Importantly, nutraceuticals also up-regulate the expression of tumor-suppressive microRNAs (miRNAs) and down-regulate the expression of oncogenic miRNAs, leading to the inhibition of pancreatic cancer cell growth and pancreatic cancer stem cell self-renewal through modulation of cellular signaling network. Furthermore, nutraceuticals also regulate epigenetically deregulated DNAs and miRNAs, leading to the normalization of altered cellular signaling in pancreatic cancer cells. Therefore, nutraceuticals could have much broader use in the prevention and/or treatment of pancreatic cancer in combination with conventional chemotherapeutics. However, more in vitro mechanistic experiments, in vivo animal studies, and clinical trials are needed to realize the true value of nutraceuticals in the prevention and/or treatment of pancreatic cancer.

Comparative in vivo evaluations of curcumin and its analog difluorinated curcumin against cisplatin-induced nephrotoxicity.

Curcumin, a polyphenol, has pharmacological effects including antioxidant, anti-inflammatory and anti-cancer features. In this study, we have performed comparative in vivo evaluations of CDF (curcumin difluorinated) and curcumin in cisplatin-induced nephrotoxicity in rats. Male Wistar rats were divided into four groups: (1) Control; (2) Cisplatin (7 mg/kg body wt, intraperitoneal as a single dose); (3) Cisplatin and CDF (50 mg/rat/day; for 12 days); (4) Cisplatin and curcumin (50 mg/rat/day), for 12 days). Cisplatin treated rats exhibited kidney injury manifested by increased serum N-urea and creatinine (P < 0.001). Kidney from cisplatin treated rats also exhibited significant increase in malondialdehyde (MDA) and 8-isoprostane levels (P < 0.001). Treatment with CDF and curcumin prevented the rise in serum N-urea, creatinine, MDA and 8-isoprostane as compared to experimental control group in kidney (P < 0.05). Compared to curcumin, CDF had greater potential in suppressing cisplatin-induced pro-inflammatory factors NF-κB and COX-2 as well as downstream markers Nrf2 and HO-1 (P < 0.05) in kidney. The analysis on anion transport markers (OAT1 and OAT3) showed a similar trend (CDF > curcumin). CDF could reduce the expression of multi-drug resistance markers OCT1, OCT2, MRP2 and MRP4 to a much greater extent than curcumin (P < 0.05). We also demonstrate that CDF influenced the expression of p-mTOR, p-p70S6K1, p-4E-BP1 and p-Akt. These data suggest that CDF can potentially be used to reduce the chemotherapy induced nephrotoxicity thereby enhancing the therapeutic window of cisplatin. The results also proved that compared to curcumin, CDF has superior protective effect in nephrotoxicity.

Recent progress on nutraceutical research in prostate cancer.

Recently, nutraceuticals have received increasing attention as the agents for cancer prevention and supplement with conventional therapy. Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer-related death in men in the US. Growing evidences from epidemiological studies, in vitro experimental studies, animal studies, and clinical trials have shown that nutraceuticals could be very useful for the prevention and treatment of PCa. Several nutraceuticals including isoflavone, indole-3-carbinol, 3,3'-diindolylmethane, lycopene, (-)-epigallocatechin-3-gallate, and curcumin are known to downregulate the signal transductions in AR, Akt, NF-κB, and other signal transduction pathways which are vital for the development of PCa and the progression of PCa from androgen-sensitive to castrate-resistant PCa. Therefore, nutraceutical treatment in combination with conventional therapeutics could achieve better treatment outcome in prostate cancer therapy. Interestingly, some nutraceuticals could regulate the function of cancer stem cell (CSC)-related miRNAs and associated molecules, leading to the inhibition of prostatic CSCs which are responsible for drug resistance, tumor progression, and recurrence of PCa. Hence, nutraceuticals may serve as powerful agents for the prevention of PCa progression and they could also be useful in combination with chemotherapeutics or radiotherapy. Such strategy could become a promising newer approach for the treatment of metastatic PCa with better treatment outcome by improving overall survival.

Plant polyphenol induced cell death in human cancer cells involves mobilization of intracellular copper ions and reactive oxygen species generation: a mechanism for cancer chemopreventive action.

SCOPE: Anticancer polyphenolic nutraceuticals from fruits, vegetables, and spices are generally recognized as antioxidants, but can be prooxidants in the presence of copper ions. We earlier proposed a mechanism for such activity of polyphenols and now we provide data in multiple cancer cell lines in support of our hypothesis. METHODS AND RESULTS: Through multiple assays, we show that polyphenols luteolin, apigenin, epigallocatechin-3-gallate, and resveratrol are able to inhibit cell proliferation and induce apoptosis in different cancer cell lines. Such cell death is prevented to a significant extent by cuprous chelator neocuproine and reactive oxygen species scavengers. We also show that normal breast epithelial cells, cultured in a medium supplemented with copper, become sensitized to polyphenol-induced growth inhibition. CONCLUSION: Since the concentration of copper is significantly elevated in cancer cells, our results strengthen the idea that an important anticancer mechanism of plant polyphenols is mediated through intracellular copper mobilization and reactive oxygen species generation leading to cancer cell death. Moreover, this prooxidant chemopreventive mechanism appears to be a mechanism common to several polyphenols with diverse chemical structures and explains the preferential cytotoxicity of these compounds toward cancer cells.

Epigenetic regulation of miRNA-cancer stem cells nexus by nutraceuticals.

Nutraceuticals, the bioactive food components represented by many naturally occurring dietary compounds, have been investigated for a few decades for their numerous beneficial effects, including their anticancer properties. The initial interest in the cancer-preventing/therapeutic ability of these agents was based on their ability to affect multiple signaling pathways that are deregulated in cancer cells. With a shift in the focus of cancer research to the emerging areas such as epigenetic regulation, microRNAs (miRNAs) and the cancer stem cells (CSCs), nutraceuticals initially appeared out of place. However, research investigations over the last several years have slowly but firmly presented evidence that supports a relevance of these agents in modern day research. While nutraceuticals are increasingly being realized to alter miRNA/CSCs expression and function, the molecular mechanism(s) are not very clearly understood. Epigenetic regulation is one mechanism by which these agents exert their anticancer effects. In this focused mini review, we summarize our current understanding of epigenetic regulation of miRNAs and CSCs by nutraceuticals. We discuss both direct and indirect evidences that support such an activity of these compounds.

Radioprotection of lung tissue by soy isoflavones.

INTRODUCTION: Radiation-induced pneumonitis and fibrosis have restricted radiotherapy for lung cancer. In a preclinical lung tumor model, soy isoflavones showed the potential to enhance radiation damage in tumor nodules and simultaneously protect normal lung from radiation injury. We have further dissected the role of soy isoflavones in the radioprotection of lung tissue. METHODS: Naive Balb/c mice were treated with oral soy isoflavones for 3 days before and up to 4 months after radiation. Radiation was administered to the left lung at 12 Gy. Mice were monitored for toxicity and breathing rates at 2, 3, and 4 months after radiation. Lung tissues were processed for histology for in situ evaluation of response. RESULTS: Radiation caused damage to normal hair follicles, leading to hair loss in the irradiated left thoracic area. Supplementation with soy isoflavones protected mice against radiation-induced skin injury and hair loss. Lung irradiation also caused an increase in mouse breathing rate that was more pronounced by 4 months after radiation, probably because of the late effects of radiation-induced injury to normal lung tissue. However, this effect was mitigated by soy isoflavones. Histological examination of irradiated lungs revealed a chronic inflammatory infiltration involving alveoli and bronchioles and a progressive increase in fibrosis. These adverse effects of radiation were alleviated by soy isoflavones. CONCLUSION: Soy isoflavones given pre- and postradiation protected the lungs against adverse effects of radiation including skin injury, hair loss, increased breathing rates, inflammation, pneumonitis and fibrosis, providing evidence for a radioprotective effect of soy.

Perspectives on the role of isoflavones in prostate cancer.

Isoflavones have been investigated in detail for their role in the prevention and therapy of prostate cancer. This is primarily because of the overwhelming data connecting high dietary isoflavone intake with reduced risk of developing prostate cancer. A number of investigations have evaluated the mechanism(s) of anticancer action of isoflavones such as genistein, daidzein, biochanin A, equol, etc., in various prostate cancer models, both in vitro and in vivo. Genistein quickly jumped to the forefront of isoflavone cancer research, but the initial enthusiasm was followed by reports on its contradictory prometastatic and tumor-promoting effects. Use of soy isoflavone mixture has been advocated as an alternative, wherein daidzein can negate harmful effects of genistein. Recent research indicates a novel role of genistein and other isoflavones in the potentiation of radiation therapy, epigenetic regulation of key tumor suppressors and oncogenes, and the modulation of miRNAs, epithelial-to-mesenchymal transition, and cancer stem cells, which has renewed the interest of cancer researchers in this class of anticancer compounds. This comprehensive review article summarizes our current understanding of the role of isoflavones in prostate cancer research.

Difluorinated-curcumin (CDF) restores PTEN expression in colon cancer cells by down-regulating miR-21.

Despite recent advancement in medicine, nearly 50% of patients with colorectal cancer show recurrence of the disease. Although the reasons for the high relapse are not fully understood, the presence of chemo- and radiotherapy-resistant cancer stem/stem-like cells, where many oncomirs like microRNA-21 (miR-21) are upregulated, could be one of the underlying causes. miR-21 regulates the processes of invasion and metastasis by downregulating multiple tumor/metastatic suppressor genes including PTEN (phosphatase and tensin homolog). Tumor suppressor protein PTEN controls self-renewal of stem cells. Indeed, our current data demonstrate a marked downregulation of PTEN in SCID mice xenografts of miR-21 over-expressing colon cancer HCT116 cells. Colonospheres that are highly enriched in cancer stem/stem like cells reveal increased miR-21 expression and decreased PTEN. Difluorinated curcumin (CDF), a novel analog of the dietary ingredient curcumin, which has been shown to inhibit the growth of 5-Flurouracil + Oxaliplatin resistant colon cancer cells, downregulated miR-21 in chemo-resistant colon cancer HCT116 and HT-29 cells and restored PTEN levels with subsequent reduction in Akt phosphorylation. Similar results were also observed in metastatic colon cancer SW620 cells. Since PTEN-Akt confers drug resistance to different malignancies including colorectal cancer, our observation of normalization of miR-21-PTEN-Akt pathway by CDF suggests that the compound could be a potential therapeutic agent for chemotherapy-resistant colorectal cancer.

Regulating miRNA by natural agents as a new strategy for cancer treatment.

MicroRNAs (miRNAs) are small single-strand non-coding endogenous RNAs that regulate gene expression by multiple mechanisms. Recent evidence suggests that miRNAs are critically involved in the pathogenesis, evolution, and progression of cancer. The miRNAs are also crucial for the regulation of cancer stem cells (CSCs). In addition, miRNAs are known to control the processes of Epithelial-to-Mesenchymal Transition (EMT) of cancer cells. This evidence suggests that miRNAs could serve as targets in cancer treatment, and as such manipulating miRNAs could be useful for the killing CSCs or reversal of EMT phenotype of cancer cells. Hence, targeting miRNAs, which are deregulated in cancer, could be a promising strategy for cancer therapy. Recently, the regulation of miRNAs by natural, nontoxic chemopreventive agents including curcumin, resveratrol, isoflavones, (-)-epigallocatechin-3-gallate (EGCG), lycopene, 3,3'- diindolylmethane (DIM), and indole-3-carbinol (I3C) has been described. Therefore, natural agents could inhibit cancer progression, increase drug sensitivity, reverse EMT, and prevent metastasis though modulation of miRNAs, which will provide a newer therapeutic approach for cancer treatment especially when combined with conventional therapeutics.

Down-regulation of miR-21 Induces Differentiation of Chemoresistant Colon Cancer Cells and Enhances Susceptibility to Therapeutic Regimens.

MicroRNAs are endogenous posttranscriptional modulators that negatively control the expression of their target genes and play an important role in the development and progression of many malignancies, including colorectal carcinoma. In particular, expression of microRNA-21 (miR-21) is greatly increased in chemotherapy-resistant (CR) colon cancer cells that are enriched in undifferentiated cancer stem/stem-like cells (CSCs/CSLCs). We hypothesize that miR-21 plays a critical role in regulating differentiation of CR colon cancer cells. Indeed, we observed that downregulation of miR-21 in CR colon cancer cells (HCT-116 or HT-29) by antisense miR-21 induced differentiation, as evidenced by marked increases in cytokeratin-20 (CK-20) expression and alkaline phosphatase activity. These changes were accompanied by a significant reduction in the expression of colon CSC/CSLC marker CD44, colonosphere formation, and T-cell factor/lymphoid enhancer factor (TCF/LEF) activity but increased the expression of proapoptotic programmed cell death 4 gene. Induction of differentiation greatly increased sensitivity of CR colon cancer cells to the growth inhibitory properties of all three regimens tested: 5-fluorouracil + oxaliplatin (FUOX), difluorinated curcumin (CDF), and the combination of CDF and FUOX. However, the magnitude of inhibition of growth by either CDF (75%) alone or CDF + FUOX (80%) was much higher than that observed with only FUOX (40%). Growth inhibition by CDF and CDF + FUOX in differentiating CR colon cancer cells was associated with a 98% to 99% reduction in the expression of CD44 and epidermal growth factor receptor (EGFR). However, down-regulation of CK-20 in CR colon cancer cells produced no significant change in cellular growth in the absence or presence of FUOX, when compared with the corresponding controls. The current observation suggests that CDF and CDF + FUOX are highly effective in inhibiting growth and reducing colon CSCs/CSLCs in anti-miR-21-induced differentiating CR colon cancer cells and supports our contention that differentiation enhances susceptibility of CR cancer cells to conventional and nonconventional therapeutic regimen.

Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment.

Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF) has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC) cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy.

Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice.

Charcot-Marie-Tooth disease type 1B is caused by mutations in myelin protein zero. R98C mice, an authentic model of early onset Charcot-Marie-Tooth disease type 1B, develop neuropathy in part because the misfolded mutant myelin protein zero is retained in the endoplasmic reticulum where it activates the unfolded protein response. Because oral curcumin, a component of the spice turmeric, has been shown to relieve endoplasmic reticulum stress and decrease the activation of the unfolded protein response, we treated R98C mutant mice with daily gastric lavage of curcumin or curcumin derivatives starting at 4 days of age and analysed them for clinical disability, electrophysiological parameters and peripheral nerve morphology. Heterozygous R98C mice treated with curcumin dissolved in sesame oil or phosphatidylcholine curcumin performed as well as wild-type littermates on a rotarod test and had increased numbers of large-diameter axons in their sciatic nerves. Treatment with the latter two compounds also increased compound muscle action potential amplitudes and the innervation of neuromuscular junctions in both heterozygous and homozygous R98C animals, but it did not improve nerve conduction velocity, myelin thickness, G-ratios or myelin period. The expression of c-Jun and suppressed cAMP-inducible POU (SCIP)-transcription factors that inhibit myelination when overexpressed-was also decreased by treatment. Consistent with its role in reducing endoplasmic reticulum stress, treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin was associated with decreased X-box binding protein (XBP1) splicing. Taken together, these data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response and by promoting Schwann cell differentiation.

From body art to anticancer activities: perspectives on medicinal properties of henna.

Nature has been a rich source of therapeutic agents for thousands of years and an impressive number of modern drugs have been isolated from natural sources based on the uses of these plants in traditional medicine. Henna is one such plant commonly known as Persian Henna or Lawsonia inermis, a bushy, flowering tree, commonly found in Australia, Asia and along the Mediterranean coasts of Africa. Paste made from the leaves of Henna plant has been used since the Bronze Age to dye skin, hairs and fingernails especially at the times of festivals. In recent times henna paste has been used for body art paintings and designs in western countries. Despite such widespread use in dyeing and body art painting, Henna extracts and constituents possess numerous biological activities including antioxidant, anti-inflammatory, antibacterial and anticancer activities. The active coloring and biologically active principle of Henna is found to be Lawsone (2- hydroxy-1, 4-naphthoquinone) which can serve as a starting building block for synthesizing large number of therapeutically useful compounds including Atovaquone, Lapachol and Dichloroallyl lawsone which have been shown to possess potent anticancer activities. Some other analogs of Lawsone have been found to exhibit other beneficial biological properties such as antioxidant, anti-inflammatory, antitubercular and antimalarial. The ability of Lawsone to undergo the redox cycling and chelation of trace metal ions has been thought to be partially responsible for some of its biological activities. Despite such diverse biological properties and potent anticancer activities the compound has remained largely unexplored and hence in the present review we have summarized the chemistry and biological activities of Lawsone along with its analogs and metal complexes.