Current Drug Targets (v.13, #14)

Inflammation is a risk factor for cancer development in several tissues. In the colorectum, inflammatory bowel disease (ulcerative colitis and Crohn's disease) is a longstanding inflammatory disease with increased risk for colorectal cancer (CRC). Several molecular events involving in chronic inflammatory process contribute to multi-stage carcinogenesis of CRC in the inflamed colon. They include alterations in production of reactive oxygen and nitrogen species, upregulation of pro-inflammatory cytokines and inflammatory enzymes, and intestinal immune system. In this short review, experimental animal models of inflammation-associated CRC are described. Also, some preclinical data on chemoprevention of inflammation-associated CRC by astaxanthin and a specific inhibitor of nitric oxide synthase using these inflammation- related -CRC models is briefly introduced.

Single Dose Oral Pharmacokinetic Profile of α-Mangostin in Mice by Atulkumar Ramaiya, Gongbo Li, Sakina M. Petiwala, Jeremy J. Johnson (1698-1704).
The mangosteen fruit (Garcinia mangostana) is a rich source of dietary xanthones with the most prominent being α-mangostin. Dietary xanthones have been reported to have a variety of health promoting properties. Until now, in vivo studies on the pharmacokinetic profile of α-mangostin are limited. For this study we employed an LC/MS/MS assay to determine the pharmacokinetic properties of α-mangostin suspension in cottonseed oil in C57BL/6 Mice. Mice were administered 100 mg/kg of α-mangostin by oral gavage and the plasma levels were analyzed over a 24 hour period. We observed the degree of exposure (i.e. area under the curve) of α-mangostin to be 5,736 nmol/L/hr and the maximum plasma concentration was 1,382 nmol/L. Furthermore, we provide evidence that α-mangostin undergoes glucuronidation into monoglucuronide and diglucuronide metabolites. Our study demonstrated that α-mangostin when administered in cotton seed oil to mice at a dose equivalent to 615 mg in a 90kg human adult achieves an approximate maximum plasma concentration of 1,300 nmol/L and is detectable for up to 24 hours. Further research is needed to understand the relationship between the pharmacokinetic properties of α-mangostin following oral administration and reported health benefits.

Indole Compounds Against Breast Cancer: Recent Developments by Bernhard Biersack, Rainer Schobert (1705-1719).
Breast cancer is still the leading cause of cancer deaths among women worldwide and new therapies and drugs are continuously being conceived and explored to better control or even cure this disease. Among the most efficacious low-molecular drugs for the treatment of breast cancer are indole derivatives such as 3,3'-diindolylmethane (DIM), the structurally complex antimitotic vinca alkaloids, and the synthetic receptor tyrosine kinase inhibitor sunitinib. This review is to give an insight into the latest developments in the field of indole based drugs against breast cancers with a focus on those derived from natural products and on their targets and modes of action. Pertinent literature is covered from 2007 up to 2012.

Anticarcinogenic Actions of Tributyrin, A Butyric Acid Prodrug by Renato Heidor, Juliana Festa Ortega, Aline de Conti, Thomas Prates Ong, Fernando Salvador Moreno (1720-1729).
Bioactive food compounds (BFCs) exhibit potential anticarcinogenic effects that deserve to be explored. Butyric acid (BA) is considered a promising BFC and has been used in clinical trials; however, its short half-life considerably restricts its therapeutic application. Tributyrin (TB), a BA prodrug present in milk fat and honey, has more favorable pharmacokinetic properties than BA, and its oral administration is also better tolerated. In vitro and in vivo studies have shown that TB acts on multiple anticancer cellular and molecular targets without affecting non-cancerous cells. Among the TB mechanisms of action, the induction of apoptosis and cell differentiation and the modulation of epigenetic mechanisms are notable. Due to its anticarcinogenic potential, strategies as lipid emulsions, nanoparticles, or structured lipids containing TB are currently being developed to improve its organoleptic characteristics and bioavailability. In addition, TB has minimal toxicity, making it an excellent candidate for combination therapy with other agents for the control of cancer. Despite the lack of data available in the literature, TB is a promising molecule for anticancer strategies. Therefore, additional preclinical and clinical studies should be performed using TB to elucidate its molecular targets and anticarcinogenic potential.

Ent-11α-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F) is a chemical compound isolated from Pteris semipinnata L (PsL), a Chinese traditional herb. 5F has been known to exert antitumor activity in several kinds of human malignant cancer cells by leading cancer cell to apoptosis. 5F translocated Bax into the mitochondria, down-regulated Bcl-2, activated caspase-9 and caspase-3, released cytochrome c into the cytosol and translocated AIF from the mitochondria to the nucleus. The presentation of a wild-type p53 in the cancer cells facilitated cancer cells sensitive to the 5F treatment. 5F induces apoptosis of cancer cells by inhibiting NF-κB activation/induction, which leading to the decrease of Bcl-2 but the increase of Bax and Bak. MAPK kinases and Akt are also involved in process of 5F inducing cancer cell apoptosis. In lung cancer, 5F activated ERK1/2 and the inhibition of ERK1/2 suppressed 5F-mediated changes in apoptotic molecules. 5F activated Akt and suggested that Akt activation was anti-apoptotic rather than pro-apoptotic. However, in anaplastic thyroid carcinoma, JNK activation was related to cell death induced by 5F. ERK and p38 were also activated but as survival signals in response to 5F treatment to counteract the induction of cell death. Collectively, 5F is effective against several malignant cancers both in vivo and in vitro with minimal side effects. It induces apoptosis through the mitochondrialmediated pathway, in which regulation of Bcl-2 family proteins expression, the activation of MAPK and inactivation of NF-κB are critical. The good ability of 5F to inhibit cancer cells makes it in line with the successful development of other anti-tumor agents.

A Prooxidant Mechanism for the Anticancer and Chemopreventive Properties of Plant Polyphenols by Husain Yar Khan, Haseeb Zubair, Mohd Fahad Ullah, Aamir Ahmad, Sheikh Mumtaz Hadi (1738-1749).
Plant-derived polyphenols, a prominent class of phytochemicals, are considered important components of human diet. A number of them are known to possess chemopreventive and therapeutic properties against various diseases including cancer. Several studies using cancer cell lines and animal models of carcinogenesis have shown that a wide range of polyphenols possess anticancer and apoptosis-inducing properties. Notably, an important aspect of the chemopreventive action of polyphenols is their differential activity in selectively targeting cancer cells while sparing normal cells. However, the mechanism through which polyphenols modulate their cancer cell selective anticancer effects has not been clearly delineated. In this regard, identification of a definitive anticancer mechanism of polyphenols would contribute to establish them as potent lead compounds for the synthesis of novel anticancer drugs. Although polyphenols are generally recognized as antioxidants, they also act as prooxidants inducing DNA degradation in the presence of metal ions such as copper. Based on our own observations and those of others, a mechanism for the anticancer properties of polyphenols that involves mobilization of chromatin-bound copper and consequent prooxidant action leading to cell death, was proposed. Since it is known that tissue and cellular copper levels are significantly elevated in a number of malignancies, cancer cells would be more subject to redox cycling between copper ions and polyphenols to generate reactive oxygen species (ROS) responsible for DNA breakage. This review discusses such a copper-dependent prooxidant mechanism of action of polyphenols that accounts for their observed chemopreventive properties, as also for their preferential cytotoxicity towards cancer cells.

Genistein Inhibits Cell Growth and Induces Apoptosis Through Up-regulation of miR-34a in Pancreatic Cancer Cells by Jun Xia, Qiaoling Duan, Aamir Ahmad, Bin Bao, Sanjeev Banerjee, Ying Shi, Jia Ma, Jian Geng, Zhiwen Chen, KM Wahidur Rahman, Lucio Miele, Fazlul H Sarkar, Zhiwei Wang (1750-1756).
Pancreatic cancer (PC) is the fourth most common cause of cancer-related deaths in the United States, suggesting that designing novel therapeutic strategy is required to improve the survival outcome of patients diagnosed with PC. Recently, microRNAs (miRNA) have been found to be involved in the regulation of multiple aspects of tumor development and progression including PC. In this study, we investigate whether miR-34a plays a critical role in the control of cell growth and apoptosis in PC cells. We found that Re-expression (forced expression) of miR-34a inhibits cell growth and induces apoptosis, with concomitant down-regulation of Notch-1 signaling pathway, one of the target of miR-34a. Moreover, treatment of PC cells with a natural compound genistein led to the up-regulation of miR-34a, resulting in the down-regulation of Notch-1, which was correlated with inhibition of cell growth, and induction of apoptosis. Our findings suggest that genistein could function as a non-toxic activator of a miRNA that can suppress the proliferation of PC cells.

Ascorbic Acid in Cancer Chemoprevention: Translational Perspectives and Efficacy by Mohammad F. Ullah, Showket H. Bhat, Eram Hussain, Faisel Abu-Duhier, Aamir Ahmad, S. M. Hadi (1757-1771).
Chemoprevention, which is referred to as the use of nontoxic natural or synthetic chemicals to intervene in multistage carcinogenesis has since decades attracted a considerable interest in plant-derived chemical constituents often termed as “phytochemicals” or sometimes as “Nutraceuticals” in case they are derived from dietary sources. A comprehensive search of the literature show that such an interest in natural product pharmacology has surged in the last 25 years and particularly risen at exponential rates since the last one decade. Phytochemicals such as curcumin (from spice turmeric), resveratrol (from red wine) and genistein (from soy) share the major efforts as indicated by overwhelming publications, despite skepticism concerning their bioavailability. Ascorbic acid (AA), the popular anti-oxidant in fruits and vegetables, has even a longer historical perspective than these dietary agents as for more than 35 years; there had been lingering questions about the efficacy of AA in cancer therapy. The footprints of AA from “scurvy” to “cancer” though complex seems to carry potential provided the puzzle could be set right. The use of AA in cancer treatment has been debated extensively as evident from the literature but surprisingly the complementing early phase bench work on the mechanistic studies for anticancer action was rather retarded. Proposed mechanisms of action for AA in the prevention and treatment of cancer includes antioxidant as well as pro-oxidant properties, stimulation of the immune system, altering carcinogen metabolism, enhancement of collagen synthesis necessary for tumor encapsulation and interference with cancer cell signaling. The observation that the intravenous administration of AA enhances its bioavailability to the extent of deriving pharmacological benefits against cancer has in recent years partially supported the clinical plausibility (efficacy) of AA towards realizing its translational advantage. Here, we provide an overview of AA with regard to its potential in the management of cancer disease.

Baicalein - An Intriguing Therapeutic Phytochemical in Pancreatic Cancer by Graham Donald, Kathleen Hertzer, Guido Eibl (1772-1776).
Despite advances in therapy for many of the most common cancers, advances which have led to corresponding improvements in survival rates, progress on the pancreatic cancer front have been slow and mortality rates remain startlingly high. New therapeutic strategies are needed. Phytochemicals are naturally occurring, plant-based substances that have garnered much interest in the research world for their anti-cancer properties, both as therapeutics and as components of the diet for chemoprevention. One particularly ubiquitous group of phytochemicals is the polyphenolic flavonoids. Baicalein, one such flavonoid, which has been widely studied in several malignancies, shows potent activity against pancreatic adenocarcinoma in both in vitro and in vivo studies. The mechanisms by which baicalein accomplishes this have recently been elucidated, and is through an induction of apoptosis in pancreatic cancer cells that are fiercely resistant to cell death. Compounds such as baicalein, offer promise in dietary chemoprevention, as chemotherapeutic adjuvants, or as targeted therapy.

From Body Art to Anticancer Activities: Perspectives on Medicinal Properties of Henna by Rohan Pradhan, Prasad Dandawate, Alok Vyas, Subhash Padhye, Bernhard Biersack, Rainer Schobert, Aamir Ahmad, Fazlul H. Sarkar (1777-1798).
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.

Chemopreventive and Chemotherapeutic Potential of Curcumin in Breast Cancer by Dona Sinha, Jaydip Biswas, Bokyung Sung, Bharat B. Aggarwal, Anupam Bishayee (1799-1819).
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.

Mitosis-Targeting Natural Products for Cancer Prevention and Therapy by Chinthalapally V. Rao, Carla D. Kurkjian, Hiroshi Y. Yamada (1820-1830).
Mitosis is a complex process resulting in division of a cell into two daughter cells, and its failure often results in the death of the daughter cells (via apoptotic, necrotic, or proliferative/senescent death). Many chemicals that inhibit the mitotic process (anti-mitotic drugs) have proven effective for killing cancer cells in vitro and in clinical settings. Among the most studied anti-mitotic drugs are plant-origin natural products including taxanes (e.g. paclitaxel, docetaxel) and vinca alkaloids (e.g. vincristine, vinblastine), whose validated target is the spindle microtubules. With the success of these agents, efforts have been made to develop other spindle poisons as well as to improve efficacy of existing spindle poisons with structural modifications. Novel drugs and natural products that inhibit other proteins involved in mitosis (nonmicrotubule targets) have been sought in hopes of expanding available cancer-directed therapies. Recently, significant advances have been made in the understanding of mitotic mechanisms in tumor cells as well as in normal epithelial cells. These advances help us to identify and develop potential natural agents for the prevention and treatment of cancer. This review will focus on natural products that target mitotic process and/or proteins involved in mitotic progression.

Apoptosis and Autophagy Induction As Mechanism of Cancer Prevention by Naturally Occurring Dietary Agents by Eiman Mukhtar, Vaqar Mustafa Adhami, Naghma Khan, Hasan Mukhtar (1831-1841).
Nontoxic naturally occurring compounds, especially those from dietary sources, are receiving increasing consideration for prevention and treatment of diseases including cancer. There is a growing need for innovative anticancer therapies and therefore search for natural compounds with novel biological activities or antineoplastic potential is currently an important area in drug discovery. Support for this interest also comes from increasing concern over the efficacy and safety of many conventional therapies, especially those that run over a long course of time. Laboratory studies in different in vitro and in vivo systems have shown that many natural compounds possess the capacity to regulate response to oxidative stress and DNA damage, suppress angiogenesis, inhibit cell proliferation and induce autophagy and apoptosis. This review discusses the induction of apoptosis and autophagy as a mechanism of cancer prevention by some of the most studied naturally occurring dietary compounds.

Cancer Chemoprevention with Green Tea Catechins: From Bench to Bed by Yohei Shirakami, Masahito Shimizu, Hisataka Moriwaki (1842-1857).
Many epidemiological studies and a large number of experimental studies using a variety of animal models have observed that consumption or administration of green tea appears to exert cancer chemopreventive activity. Based on the results of numerous laboratory cell culture investigations, several mechanisms have been hypothesized to underlie the anti-cancer activity of green tea catechins, especially that of (-)-epigallocatechin-3-gallate (EGCG), the most abundant and active constituent in green tea. These mechanisms include promotion of anti-oxidant activity, inhibition of NF-κB and AP-1, regulation of the cell cycle, inhibition of receptor tyrosine kinase pathways, control of epigenetic modifications, and modulation of the immune system. Several recent interventional studies examining the anti-carcinogenic properties of green tea catechins in humans have yielded promising results that suggest the possibility of their application to human clinical trials. This review article analyzes the results of these studies to explicate the effects of consumption or administration of green tea and its constituents on malignancies observed to date and discuss future directions in this research field.

Targeting CSC-Related miRNAs for Cancer Therapy by Natural Agents by Bin Bao, Yiwei Li, Aamir Ahmad, Asfar S. Azmi, Ginny Bao, Shadan Ali, Sanjeev Banerjee, Dejuan Kong, Fazlul H. Sarkar (1858-1868).
The theory of cancer stem cells (CSCs) has provided evidence on fundamental clinical implications because of the involvement of CSCs in cell migration, invasion, metastasis, and treatment resistance, which leads to the poor clinical outcome of cancer patients. Therefore, targeting CSCs will provide a novel therapeutic strategy for the treatment and/or prevention of tumors. However, the regulation of CSCs and its signaling pathways during tumorigenesis are not well understood. MicroRNAs (miRNAs) have been proved to act as key regulators of the post-transcriptional regulation of genes, which involve in a wide array of biological processes including tumorigenesis. The altered expressions of miRNAs are associated with poor clinical outcome of patients diagnosed with a variety of tumors. Therefore, emerging evidence strongly suggest that miRMAs play critical roles in tumor development and progression. Emerging evidence also suggest that miRNAs participate in the regulation of tumor cell growth, migration, invasion, angiogenesis, drug resistance, and metastasis. Moreover, miRNAs such as let-7, miR-21, miR-22, miR-34, miR-101, miR-146a, and miR-200 have been found to be associated with CSC phenotype and function mediated through targeting oncogenic signaling pathways. In this article, we will discuss the role of miRNAs in the regulation of CSC phenotype and function during tumor development and progression. We will also discuss the potential role of naturally occurring agents (nutraceuticals) as potent anti-tumor agents that are believed to function by targeting CSC-related miRNAs.

DIMming Ovarian Cancer Growth by Prabodh K. Kandala, Sanjay K. Srivastava (1869-1875).
Ovarian cancer is the leading gynecologic malignancy with more than 22,000 new cases and 15,000 deaths estimated each year. It is usually detected in late stages with poor prognosis due to lack of sufficiently accurate screening tests. Epidemiological studies continue to support the notion that consumption of cruciferous vegetables reduces the risk of ovarian cancer. In the present review article, we describe the anti-cancer effects of 3, 3'-diindolylmethane (DIM), a compound present in cruciferous vegetables, against ovarian cancer. DIM targets multiple aspects of cancer such as cellcycle regulation and survival, including EGFR-JAK2-STAT3 signaling, checkpoint activation, caspase activation, endoplasmic reticulum stress, autophagy and anoikis. This broad spectrum of anti-cancer activities in conjunction with low systemic toxicity accentuates the translational value of DIM in cancer therapy. Together, our pre-clinical studies demonstrate that DIM has activity against ovarian cancer and hence should be further investigated in clinical setting to exploit its therapeutic potential.

Metformin, a widely used anti-hyperglycemic drug in the biguanide class, is currently under investigation for the prevention of cancer. Surprisingly however, considering the time and cost of clinical chemoprevention trials and the current scrutiny of cancer chemoprevention, limited attention has been given to integrating available data, identifying the subpopulations most likely to benefit, or to quantitatively understanding the potential pitfalls of biguanide chemoprevention. Herein, a physiologically-based pharmacokinetic (PBPK) and pharmacodynamic framework is proposed for integrating information on physicochemical, cell-based, animal, and human studies of various biguanides to identify gaps in knowledge and to build a systems model that may facilitate the planning of randomized cancer chemoprevention trials of metformin.

Bioavailability Challenges Associated with Development of Saponins As Therapeutic and Chemopreventive Agents by Song Gao, Sumit Basu, Zhen Yang, Arijita Deb, Ming Hu (1885-1899).
Saponins, a major class of natural phytochemicals, hold great promises for being developed into chemopreventive and chemotherapeutic drugs. However, one of the major factors limiting their pharmacological effects in vivo is poor bioavailability. This paper reviews the factors that determine the absorption and bioavailability of saponins including their physicochemical properties, and their absorption and disposition in the gastrointestinal tract. A critical review of the current research papers suggests that poor permeability and microflora hydrolysis of saponins are the primary factors that limit their bioavailabilities. Future investigations should be directed towards further optimization of the bioavailability of saponins to enhance their chemopreventive and chemotherapeutic effects in vivo.

The Caribbean tropical tree, Pimenta dioica has been used for a variety of human endeavors, such as in perfumery industry, food spice, as a natural pesticide, and in folk medicine. Discovered in Jamaica during the voyages of Christopher Columbus, the dried unripe berries of P. dioica also known as Allspice can be found in all continents with unique names in over 50 languages. Systematic investigation of aromatic constituents of Pimenta leaves and its unripe berries, Allspice, have resulted in discovery of many and novel aromatic compounds, mostly glycosides and polyphenols that show antibacterial, hypotensive, anti-neuralgic and analgesic properties. Recent studies have shown two of the known compounds isolated from Allspice, Eugenol and Gallic acid have selective antiproliferative and anti-tumor properties on human cancer cells and their animal models. New characterization of novel compounds such as Ericifolin from the aqueous extract of Allspice berries show potent anti-prostate cancer and anti-breast cancer properties that can be verified in vitro as well as in vivo. Considering its purity, mostly available as “organically grown” berries, availability at low cost, wide acceptance in culinary delights of many cultures world-wide, Allspice may have an additional space in most households, in their medicine cabinets.

Androgen Receptor in Human Health: A Potential Therapeutic Target by Hifzur Rahman Siddique, Sanjeev Nanda, Aijaz Parray, Mohammad Saleem (1907-1916).
Androgen is a key for the activation of Androgen Receptor (AR) in most of the disease conditions, however androgen-independent activation of AR is also found in aggressive type human malignancies. An intense search for the inhibitors of AR is underway to cure AR-dependent diseases. In addition to targeting various components of AR signaling pathway, compounds which directly target AR are under preclinical and clinical investigation. Various In vitro and preclinical animal studies suggest that different natural compounds have potential to act against AR. Some natural compounds have been found to be pharmacologically effective against AR irrespective of varying routs of administration viz; oral, intra-peritoneal and intravenous. This mini-review summarizes the studies conducted with different natural agents in determining their pharmacological utility against AR signaling.

Breast cancer is the most common cancer in women in the United States, with African-American (AA) women showing significantly higher rates than Caucasian-American (CA) women do. The reason for this racial disparity remains unknown, and factors that might be responsible for the differences in incidence and mortality have not been identified. One possible factor could be microRNAs (miRs), which are small noncoding regulatory RNAs involved intimately in cancer, and the expression of certain miRs may be decreased or increased in the breast tumors of AA and CA women. Therefore, modulation of miRs using natural agents could lead to the development of a novel therapeutic strategy to treat aggressive forms of breast cancer in women of different racial backgrounds. The function of natural agents in the regulation of miRs has not been investigated extensively. In this review, we will discuss the potential role of naturally occurring agents as potent antitumor agents thought to function by targeting miRs as contributing factors to the disparity in breast cancer between AA and CA women.