Regulation of Cell Signaling Pathways by Genistein in Different Cancers: Progress, Prospects and Pitfalls.

On the translational front, integrative genomic approaches have spurred the identification of diverse mechanisms of drug resistance, tumor heterogeneity, metastasis and emerging preclinical targets. Recent breakthroughs in oncogenic cell signaling pathways have forged new links and multi-disciplinary researchers have unraveled different facets of signaling landscapes. Natural product research has witnessed breakneck developments mainly in the context of the ever-expanding list of bioactive components having significantly pharmacological properties. Genistein has gradually gained appreciation because of its multifaceted roles in the prevention and inhibition of carcinogenesis and metastasis. More importantly, the entry of genistein into various phases of clinical trials substantiates the medicinal and pharmacological significance of genistein in cancer chemoprevention. In this review, we have attempted to summarize how genistein regulated different oncogenic pathways in carcinogenesis and metastasis. Furthermore, genistein-mediated regulation of non-coding RNAs is also an interesting feature that has been included in this review to realistically analyze how genistein-mediated control of miRNAs, lncRNAs and circRNAs influence carcinogenesis. In the later sections, we have provided a summary of clinical trials related to genistein for cancer prevention/inhibition. However, apart from the optimistic approaches to further investigate genistein-mediated cancer-inhibitory effects, certain hints have emerged which underscore the pro-metastatic role of genistein. Therefore, the pro-metastatic role of genistein in different cancers should be rationally tested in a broader context because these properties in the future may reduce the enthusiasm in the quest to pursue genistein as a potent cancer chemopreventive agent.

Epigenetic deregulation in cancer: Enzyme players and non-coding RNAs.

Data obtained from cutting-edge research have shown that deregulated epigenetic marks are critical hallmarks of cancer. Rapidly emerging scientific evidence has helped in developing a proper understanding of the mechanisms leading to control of cellular functions, from changes in chromatin accessibility, transcription and translation, and in post-translational modifications. Firstly, mechanisms of DNA methylation and demethylation are introduced, as well as modifications of DNA and RNA, with particular focus on N6-methyladenosine (m6A), discussing the effects of these modifications in normal cells and in malignancies. Then, chromatin modifying proteins and remodelling complexes are discussed. Many enzymes and accessory proteins in these complexes have been found mutated or have undergone differential splicing, leading to defective protein complexes. Epigenetic mechanisms acting on nucleosomes by polycomb repressive complexes and on chromatin by SWI/SNF complexes on nucleosome assembly/disassembly, as well as main mutated genes linked to cancers, are reviewed. Among enzymes acting on histones and other proteins erasing the reversible modifications are histone deacetylases (HDACs). Sirtuins are of interest since most of these enzymes not only deacylate histones and other proteins, but also post-translationally modify proteins adding a Mono-ADP-ribose (MAR) moiety. MAR can be read by MACRO-domain containing proteins such as histone MacroH2A1, with specific function in chromatin assembly. Finally, recent advances are presented on non-coding RNAs with a scaffold function, prospecting their role in assembly of chromatin modifying complexes, recruiting enzyme players to chromatin regions. Lastly, the imbalance in metabolites production due to mitochondrial dysfunction is presented, with the potential of these metabolites to inhibit enzymes, either writers, readers or erasers of epitranscriptome marks. In the perspectives, studies are overwied on drugs under development aiming to limit excessive enzyme activities and to reactivate chromatin modifying complexes, for therapeutic application. This knowledge may lead to novel drugs and personalised medicine for cancer patients.

Realizing the Potential of Blueberry as Natural Inhibitor of Metastasis and Powerful Apoptosis Inducer: Tapping the Treasure Trove for Effective Regulation of Cell Signaling Pathways.

Blueberries belong to the genus Vaccinium of the family Ericaceae. Rapidly accumulating experimentally verified data is uncovering the tremendous pharmacological properties of biologically active constituents of blueberries against different diseases. Our rapidly evolving knowledge about the multifaceted nature of cancer has opened new horizons to search for different strategies to target multiple effectors of oncogenic networks to effectively inhibit cancer onset and progression. Excitingly, whole blueberry powder and various bioactive constituents (pterostilbene, malvidin-3-galactoside) of blueberries have been shown to efficiently inhibit metastasis in animal models. These results are encouraging and future studies must focus on the identification of cell signaling pathways effectively modulated by blueberries in different cancers. It seems exciting to note that researchers are focusing on metastasis inhibitory effects of blueberry; however, to reap full benefits, it is necessary to take a step back and critically re-interpret the mechanisms used by active components of blueberry to inhibit or prevent metastasis. JAK/STAT, TGF/SMAD, Notch, SHH/GLI, and Wnt/ ß-Catenin have been shown to be directly involved in the regulation of metastasis. However, because of limited studies, it is difficult to critically assess the true potential of blueberry. Loss of apoptosis, metastasis and deregulation of signaling pathways are branching trajectories of molecular oncology. Accordingly, we have to emphasize on these essential facets to realistically claim blueberry as "Superfood". Different clinical trials have been conducted to gather clinical evidence about the chemopreventive role of blueberry or its bioactive components in cancer patients. But it seems clear that because of the lack of sufficient proof-of-concept studies, we cannot extract significant information about the transition of blueberry into the next phases of clinical trials. Overview of the existing scientific evidence revealed visible knowledge gaps and a better understanding of the targets of blueberry will be helpful in efficient and meaningful translation of laboratory findings to clinically effective therapeutics.

Regulation of signaling pathways by Ampelopsin (Dihydromyricetin) in different cancers: exploring the highways and byways less travelled.

Ampelopsin or Dihydromyricetin is gradually emerging as a high-quality natural product because of its ability to modulate wide-ranging signaling pathways. Ampelopsin (Dihydromyricetin) has been reported to effectively modulate growth factor receptor (VEGFR2 and PDGFRß) mediated signaling,  TRAIL/TRAIL-R pathway, JAK/STAT and mTOR-driven signaling in different cancers. Ampelopsin (Dihydromyricetin) has also been shown to exert inhibitory effects on the versatile regulators which trigger EMT (Epithelial-to-Mesenchymal Transition). Findings obtained from in-vitro studies are encouraging and there is a need to comprehensively analyze how Ampelopsin (Dihydromyricetin) inhibits tumor growth in different cancer models. Better knowledge of efficacy of Ampelopsin (Dihydromyricetin) in tumor bearing mice will be helpful in maximizing its translational potential.

MicroRNA-143 as a new weapon against cancer: overview of the mechanistic insights and long non-coding RNA mediated regulation of miRNA-143 in different cancers.

Central dogma of molecular biology, a term coined by Francis Crick in 1958 was considered to be the cornerstone of molecular biology unless molecular biologists challenged the idea after ground-breaking discovery of non-coding RNAs. Discovery of microRNAs marked a new era and revolutionized our understanding related to puzzling mysteries about intermediate steps between transcription and translation. Technological advancements have spawned a multitude of platforms for profiling of long-noncoding RNAs and miRNAs in different cancers. Detailed investigation of mRNA targets of miRNAs has enabled high-order analyses of interconnected networks and revealed affected pathways in different cancers. miR-143 has emerged as a multi-talented tumor suppressor microRNA having considerable ability to inhibit and prevent cancer via regulation of myriad of oncogenes. In this review, we will summarize most recent evidence related to characteristically unique ability of miR-143 to target different oncogenic mRNAs in different cancers. We will also comprehensively discuss how scientists have identified multiple long non-coding RNAs reportedly involved in promoting the expression of oncogenes by interfering with miR-143 mediated targeting of these oncogenes. Because of excellent ability of miR-143 to effectively target oncogenic mRNAs, researchers have started to focus on use of miR-143 mimics to restore expression of miR-143 in various cancers.

Interplay between epigenetic abnormalities and deregulated expression of microRNAs in cancer.

Epigenetic abnormalities and aberrant expression of non-coding RNAs are two emerging features of cancer cells, both of which are responsible for deregulated gene expression. In this review, we describe the interplay between the two. Specific themes include epigenetic silencing of tumor suppressor miRNAs, epigenetic activation of oncogenic miRNAs, epigenetic aberrations caused by miRNAs, and naturally occurring compounds which modulate miRNA expression through epigenetic mechanisms.

MicroRNA regulation of TRAIL mediated signaling in different cancers: Control of micro steering wheels during the journey from bench-top to the bedside.

Large-scale sequencing methodologies have helped us identify numerous genomic alterations and we have started to scratch the surface of many new targets for treatment of cancer and the associated predictive biomarkers. TRAIL (TNF-related apoptosis-inducing ligand) is a highly appreciated anti-cancer molecule because of its ability to selectively target cancer cells. However, confluence of information suggests that cancer cells develop resistance against TRAIL-based therapeutics. It is being realized that overexpression of anti-apoptotic proteins and inactivation of pro-apoptotic proteins significantly impairs TRAIL triggered apoptosis, particularly in clinical settings. Re-balancing of pro-and anti-apoptotic proteins and upregulation of death receptors with functionally active extrinsic and intrinsic apoptotic pathways are necessary to sensitize cancer cells to TRAIL based therapeutics. microRNAs (miRNAs) are involved in regulation of myriad of molecular processes and characterized into oncogenic and tumor suppressor miRNAs. Accumulating data has identified miRNAs which positively or negatively regulate TRAIL mediated signaling in cancer cells, helping us understand different steps at which TRAIL-mediated apoptotic signaling can be targeted. Here, we assess the status of our understanding of the mechanisms related to miRNA regulation of TRAIL mediated signaling, as well as the existing gaps therein, and discuss the challenges and opportunities that will help us get closer to personalized medicine.

Oxidative stress-modulating drugs have preferential anticancer effects - involving the regulation of apoptosis, DNA damage, endoplasmic reticulum stress, autophagy, metabolism, and migration.

To achieve preferential effects against cancer cells but less damage to normal cells is one of the main challenges of cancer research. In this review, we explore the roles and relationships of oxidative stress-mediated apoptosis, DNA damage, ER stress, autophagy, metabolism, and migration of ROS-modulating anticancer drugs. Understanding preferential anticancer effects in more detail will improve chemotherapeutic approaches that are based on ROS-modulating drugs in cancer treatments.

Interplay of long non-coding RNAs and TGF/SMAD signaling in different cancers.

Based on the exciting insights gleaned from decades of ground-breaking research, it has become evident that deregulated signaling pathways play instrumental role in cancer development and progression. Interestingly discovery of non-coding RNAs has revolutionized our understanding related to transcription, post-transcription and translation. Modern era has witnessed landmark discoveries in the field of molecular cancer and non-coding RNA biology has undergone tremendous broadening. There has been an exponential growth in the list of publications related to non-coding RNAs and overwhelmingly increasing classes of non-coding RNAs are adding new layers of complexity to already complicated nature of cancer. Regulation of TGF/SMAD signaling by miRNAs and LncRNAs has opened new horizons for therapeutic targeting of TGF/SMAD pathway. In this review we have set spotlight on central role of LncRNAs in modulation of TGF/SMAD pathway. Major proportion of the available evidence is underlining positive role of LncRNAs in contextual regulation of TGF/SMAD pathway. LncRNAs are vital to these regulatory networks because they provide a background support to make the TGF/SMAD mediated intracellular signaling more smooth or make transduction cascade more flexible in response to cues from extracellular environment. Therefore, in accordance with this notion, MALAT1, OIP5-AS1, MIR100HG, HOTAIR, ANRIL, PVT1, AFAP1-AS1, SPRY4-IT, ZEB2NAT, TUG1 and Lnc-SNHG1 have been reported to positively regulate TGF/SMAD signaling. In this review, we have focused on the regulation of TGF/SMAD signaling by LncRNAs and how these non-coding RNAs can be therapeutically exploited. Short-interfering RNA (siRNA) and natural products are currently being tested for efficacy against different LncRNAs. Nanotechnological strategies to efficiently deliver LncRNA-targeting siRNAs are also currently being investigated in different cancers.

TRAIL, Wnt, Sonic Hedgehog, TGFß, and miRNA Signalings Are Potential Targets for Oral Cancer Therapy.

Clinical studies and cancer cell models emphasize the importance of targeting therapies for oral cancer. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is highly expressed in cancer, and is a selective killing ligand for oral cancer. Signaling proteins in the wingless-type mouse mammary tumor virus (MMTV) integration site family (Wnt), Sonic hedgehog (SHH), and transforming growth factor ß (TGFß) pathways may regulate cell proliferation, migration, and apoptosis. Accordingly, the genes encoding these signaling proteins are potential targets for oral cancer therapy. In this review, we focus on recent advances in targeting therapies for oral cancer and discuss the gene targets within TRAIL, Wnt, SHH, and TGFß signaling for oral cancer therapies. Oncogenic microRNAs (miRNAs) and tumor suppressor miRNAs targeting the genes encoding these signaling proteins are summarized, and the interactions between Wnt, SHH, TGFß, and miRNAs are interpreted. With suitable combination treatments, synergistic effects are expected to improve targeting therapies for oral cancer.

Oleuropein and Cancer Chemoprevention: The Link is Hot.

Cancer comprises a collection of related diseases characterized by the existence of altered cellular pathways resulting in an abnormal tendency for uncontrolled growth. A broad spectrum, coordinated, and personalized approach focused on targeting diverse oncogenic pathways with low toxicity and economic natural compounds can provide a real benefit as a chemopreventive and/or treatment of this complex disease. Oleuropein, a bioactive phenolic compound mainly present in olive oil and other natural sources, has been reported to modulate several oncogenic signalling pathways. This review presents and critically discusses the available literature about the anticancer and onco-suppressive activity of oleuropein and the underlying molecular mechanisms implicated in the anticarcinogenic and therapeutic effects. The existence of limitations and the promising perspectives of research on this phenolic compound are also critically analyzed and discussed.

Restoring TRAIL Induced Apoptosis Using Naturopathy. Hercules Joins Hand with Nature to Triumph Over Lernaean Hydra.

Cancer is a multifaceted disease. Our deepened knowledge about genetic and biological mechanisms of cancer cells presents an opportunity to explore the inter-individual differences in the body's ability to metabolize and respond to different nutrients. It is becoming progressively more understandable that the deregulation of several signaling pathways and the alterations in apoptotic response are some of the major determinants that underpin carcinogenesis. Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL)-mediated signaling has gained a remarkable appreciation because of its ability to selectively induce apoptosis in cancer cells leaving normal cells intact. However, technological advances have started to shed light on underlying mechanisms of resistance against TRAIL-induced apoptosis in cancer cells. The impairment of TRAIL-mediated apoptosis includes various factors ranging from the loss or down regulation of TRAIL receptors or pro-apoptotic proteins to the up regulation of anti-apoptotic proteins. Intriguingly to mention that there is an ever-increasing number of natural herbal extracts (phytometabolites), which have been explored to date for their potential action in restoring apoptosis TRAIL-mediated in cancer cells. In this review, we will highlight the progress in understanding the mechanisms opted by phenolic compounds in overcoming TRAIL resistance.

New Frontiers in Promoting TRAIL-Mediated Cell Death: Focus on Natural Sensitizers, miRNAs, and Nanotechnological Advancements.

Cancer is a multifaceted and genomically complex disease, and rapidly emerging scientific evidence is emphasizing on intra-tumor heterogeneity within subpopulations of tumor cells and rapidly developing resistance against different molecular therapeutics. There is an overwhelmingly increasing list of agents currently being tested for efficacy against cancer. In accordance with the concept that therapeutic agents must have fewer off target effects and considerable efficacy, TRAIL has emerged as one among the most deeply investigated proteins reportedly involved in differential killing of tumor cells. Considerable killing activity of TRAIL against different cancers advocated its entry into clinical trials. However, data obtained through preclinical and cell culture studies are deepening our understanding of wide-ranging mechanisms which induce resistance against TRAIL-based therapeutics. These include downregulation of death receptors, overexpression of oncogenes, inactivation of tumor suppressor genes, imbalance of pro- and anti-apoptotic proteins, and inactivation of intrinsic and extrinsic pathways. Substantial fraction of information has been added into existing pool of knowledge related to TRAIL biology and recently accumulating evidence is adding new layers to regulation of TRAIL-induced apoptosis. Certain hints have emerged underscoring miR135a-3p- and miR-143-mediated regulation of TRAIL-induced apoptosis, and natural agents have shown remarkable efficacy in improving TRAIL-based therapeutics by increasing expression of tumor suppressor miRNAs. In this review, we summarize most recent breakthroughs related to naturopathy and strategies to nanotechnologically deliver TRAIL to the target site in xenografted mice. We also set spotlight on positive and negative regulators of TRAIL-mediated signaling. Comprehensive knowledge of genetics and proteomics of TRAIL-based signaling network obtained from cancer patients of different populations will be helpful in getting a step closer to personalized medicine.

Oleuropein Mediated Targeting of Signaling Network in Cancer.

Cancer is a multifaceted and genomically complex disease. Rapidly accumulating preclinical and clinical studies are emphasizing on wide ranging molecular mechanisms that underpin cancer development, progression and metastasis. Intratumor heterogeneity, loss of apoptosis, rapidly developing resistance against molecular therapeutics and off-target effects are some of the deeply studied resistance mechanisms. Data obtained through high-throughput technologies has considerably enhanced our understanding of the intracellular signaling cascades frequently dysregulated spatio-temporally. There is an ever-expanding list of synthetic and natural agents reported to activate tumor suppressor genes and inhibit oncogenes in cancer cells. Markedly reduced tumor growth has also been documented in xenografted mice administered with phytochemicals. Oleuropein is a bioactive ingredient isolated from various sources and there is evidence of complete regression of tumors in 9- 12 days in mice orally administered with Oleuropein. In this review we summarize recent developments in use of Oleuropein as an anticancer agent. Extraction and isolation of Oleuropein and how it modulates intracellular signaling network to induce apoptosis in cancer cells. Human epidermal growth factor receptor 2 (HER2) frequently overexpressed in breast cancer cells is inhibited by Oleuropein. Interestingly, trastuzumab efficacy was notably enhanced in Oleuropein treated breast cancer cells. There is still insufficient information related to Oleuropein mediated microRNA regulation in cancer cells. We still do not have information about regulation of different signaling cascades by Oleuropein which are deregulated in cancer. Future studies must converge on a deeper analysis of target molecular network of Oleuropein and its efficacy as a tumor growth inhibitor in xenografted mice.

Is miR-34a a Well-equipped Swordsman to Conquer Temple of Molecular Oncology?

Overwhelmingly increasing advancements in miRNA biology have opened new avenues for pharmaceutical companies to initiate studies on designing effective, safe, and therapeutically active candidates using miRNA mimetics and miRNA inhibitors. In accordance with this approach, development of miravirsen and SPC3649, an LNA-based (locked nucleic acid) antisense molecule against miR-122, to treat hepatitis C has sparked interest in identifying most efficient microRNAs for journey from bench-top toward pharmaceutical industry and breakthroughs in delivery technology will pave the way to 'final frontier'. MRX34, a liposome-formulated mimic of miR-34 for treatment of metastatic cancer with liver involvement and unresectable primary liver cancer, has also entered in clinical trial. There is a successive increase in the research work related to miR-34 biology and miRNA regulation of modulators of intracellular signaling cascades. We partition this review into how miR-34a is regulated by different proteins and how Wnt- and TGF-induced intracellular signaling cascades are modulated by miR-34a. In this review, we bring to limelight how miR-34a regulates its target genes to induce apoptosis and inhibit cell proliferation as evidenced by in vitro and in vivo analysis. We also discuss miR-34 regulation of PDGFR and c-MET and recent advancements in nanotechnologically delivered miR-34a. Spotlight is also set on modulation of chemotherapeutic sensitivity by miR-34a in cancer cells using reconstruction studies. Clinical trial of miR-34 is indicative of its tremendous potential, and continuous cutting research will prove to be effective in efficiently translating laboratory findings into clinically effective therapeutics.

Penetrance and phenotypic effects of C/T polymorphism at 1595 position in exon 5 of the TRAIL gene among prostate cancer patients in Pakistani population.

It is becoming progressively more understandable that variations within the sequence of tumor suppressor genes and oncogenes may contribute to cancer progression. Increasingly it is being realized that cancer cells get resistant to pro-apoptotic signals and evidence has started to shed light on the fact that nucleotide polymorphisms may lead to suboptimal apoptotic capacity and therefore increased cancer risk. It has previously been shown that there is a relationship between C/T polymorphism at 1595 position in exon 5 of the TRAIL gene and cancer however rapidly accumulating data cannot be extrapolated to other populations due to intra- and inter-ethnic variability. The study is focused on the C/T polymorphism at 1595 position in exon 5 of the TRAIL gene in prostate cancer patients diagnosed in local population in Pakistan. 126 prostate cancer patients and 91 control subjects participated in this study. 5ml venous blood was taken from participants with informed consent. DNA was extracted using standard organic methods. PCR-RFLP analysis was done for C/T polymorphism at 1595 position in exon 5 of the TRAIL gene using site specific primers and restriction enzyme. The results were statistically evaluated in SPSS14. In this particular study it was found that there was no significant difference in major allele C genotype between patients and controls, p value > 0.05. Similar statistically non-significant difference was observed for T allele genotype in the patient and control groups. However the heterozygous genotype CT was significantly higher, p value 0.053 (-0.05), in prostate cancer patients as compared to controls. This is the first study providing a clue of relationship of C/T polymorphism role in prostate cancer development and progression in our population.

Anticancer drugs for the modulation of endoplasmic reticulum stress and oxidative stress.

Prior research has demonstrated how the endoplasmic reticulum (ER) functions as a multifunctional organelle and as a well-orchestrated protein-folding unit. It consists of sensors which detect stress-induced unfolded/misfolded proteins and it is the place where protein folding is catalyzed with chaperones. During this folding process, an immaculate disulfide bond formation requires an oxidized environment provided by the ER. Protein folding and the generation of reactive oxygen species (ROS) as a protein oxidative byproduct in ER are crosslinked. An ER stress-induced response also mediates the expression of the apoptosis-associated gene C/EBP-homologous protein (CHOP) and death receptor 5 (DR5). ER stress induces the upregulation of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor and opening new horizons for therapeutic research. These findings can be used to maximize TRAIL-induced apoptosis in xenografted mice. This review summarizes the current understanding of the interplay between ER stress and ROS. We also discuss how damage-associated molecular patterns (DAMPs) function as modulators of immunogenic cell death and how natural products and drugs have shown potential in regulating ER stress and ROS in different cancer cell lines. Drugs as inducers and inhibitors of ROS modulation may respectively exert inducible and inhibitory effects on ER stress and unfolded protein response (UPR). Reconceptualization of the molecular crosstalk among ROS modulating effectors, ER stress, and DAMPs will lead to advances in anticancer therapy.

Rutin mediated targeting of signaling machinery in cancer cells.

Progress in our understanding of molecular oncology has started to shed light on dysregulation of spatio-temporally controlled signaling pathways, inactivation of tumor suppressor genes, tumour and normal stem cell quiescence, overexpression of oncogenes, extracellular and stromal microenvironments, epigenetics and autophagy. Sequentially and characteristically it has been shown that cancer cells acquire the ability to escape from apoptotic cell death, proliferate uncontrollably, sustain angiogenesis and tactfully reconstitute intracellular pathways to avoid immune surveillance. We have attempted to provide a recent snapshot of most recent progress with emphasis on how rutin modulates wide ranging intracellular signaling cascades as evidenced by in-vitro and in-vivo research. It is worth describing that 'single-cell proteomics' analysis has further improved our understanding regarding intracellular signaling pathways frequently activated in cancer cells resistant to therapeutics and can provide biomarkers for cancer diagnosis and prognosis. Data obtained from preclinical studies will prove to be helpful for scientists to bridge basic and translational studies.

Reactive oxygen species and autophagy modulation in non-marine drugs and marine drugs.

It is becoming more understandable that an existing challenge for translational research is the development of pharmaceuticals that appropriately target reactive oxygen species (ROS)-mediated molecular networks in cancer cells. In line with this approach, there is an overwhelmingly increasing list of many non-marine drugs and marine drugs reported to be involved in inhibiting and suppressing cancer progression through ROS-mediated cell death. In this review, we describe the strategy of oxidative stress-based therapy and connect the ROS modulating effect to the regulation of apoptosis and autophagy. Finally, we focus on exploring the function and mechanism of cancer therapy by the autophagy modulators including inhibitors and inducers from non-marine drugs and marine drugs.

Anticancer activity of essential oils: targeting of protein networks in cancer cells.

Cancer is a multifaceted and genomically complex disease and research over decades has gradually and sequentially shown that essential biological mechanisms including cell cycle arrest and apoptosis are deregulated. The benefits of essential oils from different plants have started to gain appreciation as evidenced by data obtained from cancer cell lines and xenografted mice. Encouraging results obtained from preclinical studies have attracted considerable attention and various phytochemicals have entered into clinical trials.