Anti-Cancer Agents in Medicinal Chemistry (v.11, #6)
Resveratrol and Its Analogues: Promising Antitumor Agents by Xianfeng-Huang, Hai-Liang Zhu (479-490).
Resveratrol, a well-know natural product and a major component in grape, has attracted considerable attention as one ofthe most promising cancer during the past decade. Many studies have established that resveratrol can exert a broad range of biologicalactivities including ceramide-mediated proapoptotic, antineoplastic, apoptosis-inducing, etc. Most important, resveratrol has beenidentified as an effective candidate for cancer chemoprevention based on its striking inhibitory effects on cellular events associated withcancer initiation, promotion, and progression. This review describes the general properties of resveratrol and its potential effect againstcancer including its evidences as an antitumor agent in vitro, in vivo and clinically. In addition, we also summarized the structure-activityrelationship of resveratrol and its analogues regarding the antitumor effects.
Editorial [Hot Topic: Recent Advances Into the Molecular Mechanisms and Therapeutic Targeting of Hepatocellular Carcinoma (Guest Editors: Dr. Mei-Sze Chua and Li Wang)] by Mei-Sze Chua, Li Wang (491-492).
This special issue focuses on hepatocellular carcinoma (HCC), the predominant form of adult liver cancer, and also the third mostcommon cause of cancer deaths worldwide. Despite well defined major etiologies and risk factors, and recent scientific advances inunderstanding hepatocarcinogenesis, survival of patients has not improved greatly over the past three decades. This is in part due topresentation and diagnosis of HCC at the advanced stages, when most potentially curative therapies such as resection, transplantation, orpercutaneous and transarterial interventions are of limited efficacy. It is intrinsically resistant to conventional chemotherapy, and is rarelyamenable to radiotherapy, leaving patients with no effective therapeutic options and a very poor prognosis. The development of moreeffective therapeutic agents and strategies is therefore much needed to improve the clinical management and prognosis of millions of HCCpatients.HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of cirrhosis (often caused byviral hepatitis or other chronic liver diseases). Recent insights into the biology of HCC suggest that certain signaling pathways and molecularalterations are likely to play essential roles in HCC development by promoting cell growth and survival. The malignant transformationof hepatocytes is a multistep process associated with preneoplastic changes in gene expression, resulting from altered methylation of genes,the actions of hepatitis B and C viruses, and point mutations or loss of heterozygosity. Improved knowledge in these critical areas has led tothe identification of several potential therapeutic targets and has driven the development of molecularly targeted therapies. In this specialissue, we first present an introduction to the basic molecular mechanisms underlying HCC development, including emerging areas of researchsuch as small non-coding RNA molecules microRNAs and stem cells in liver cancer that hold great promise for future therapeuticapplications, followed by reviewing several promising approaches and molecular targets for the treatment of HCC. Taken together, thesemolecular approaches offer novel and potentially more efficacious avenues to improve the clinical management and prognosis of HCCpatients.The first article, “Molecular mechanisms of liver cancer”, by Dr. Wendong Huang's group, discussed important signaling moleculesregulating hepatic inflammation and liver injury and their involvement in the development of liver cancer. The second article, “MicroRNAinvolvement in hepatocellular carcinoma”, by Dr. Massimo Negrini and his colleagues, provided a comprehensive overview of the role ofsmall non-coding RNA microRNAs (miRNAs) in HCC. The article summarized the regulatory roles of miRNA on cell cycle, apoptosis,invasion and metastasis, and the β-catenin pathway, and also highlighted the value of using miRNA expression profile for HCC classificationand prognostic stratification, and their blood circulating levels as HCC biomarkers. Lastly, the therapeutic potential of miRNA for HCCtherapy was discussed. In the following article by Dr. Zhen Fan Yang's group, “Role of Stem cells in normal liver and cancer”, the authorsintroduced normal stem cells and putative cancer stem cells (CSCs) in the liver, and discussed signaling pathways, including the Bmil, Wnt/-βcatenin, Notch, PTEN, TGF-β, and sonic hedgehog pathways, that regulate pathophysiological activities of liver CSCs and the therapeuticpotential by targeting CSCs in liver cancer. Nuclear receptors (NRs) are ligand-activated transcription factors regulating a wide variety ofphysiological and pathological functions in the liver, including hepatocarcinogenesis. The next article by Drs. Guodong Li and Grace Guo,entitled “Role of class II nuclear receptors in liver carcinogenesis”, summarized the roles of class II NRs, including PPARβ, PPARβ/β,PPARβ, RARs, FXR, CAR, PXR, LXRs, TRs, and VDR, in liver carcinogenesis and their potential application in the prevention andtreatment of HCC.The poor prognosis of HCC patients is in part due to inaccurate diagnosis of HCC at an early stage. In the quest for more specific andsensitive HCC tumor markers, researchers have identified glypican-3 (GPC3) as being specifically over-expressed in HCC tumors but not innormal liver or other benign liver lesions. The article “Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma” by Dr. MarkAllegretta provided the rationale for targeting GPC3 in HCC, and suggested strategies in which the functions of GPC3 can be inhibited toachieve therapeutic effects in HCC. As alluded to by Dr. Allegretta, the relationship between GPC3 and the Wnt pathway offers excitingopportunities to target these pathways in concert for more effective, broad-spectrum therapeutic intervention. In the contribution “Points oftherapeutic intervention along the Wnt signaling pathway in hepatocellular carcinoma”, Dr. Miran Kim provided a comprehensive review ofthe many possibilities that various components of this pathway can be exploited for the treatment of HCC. Besides the critical Wnt signalingpathway, several other pathways are also major contributors towards cell proliferation, survival, metastasis, and angiogenesis in HCCdevelopment. These include the components of the receptor tyrosine kinase-activated pathways, such as the Raf, mitogen-activated proteinextracellular kinase (MEK) and extracellular signal-regulated kinase (ERK) (Raf/MEK/ERK) pathway, the phosphatidylinositol 3-kinase(PI3K)/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, the angiopoietins/Tie2 (Ang/Tie2) system, and the Janus kinase(Jak)-signal transducer/activator of transcription factor (Stat) (Jak/Stat) pathway. These pathways lie downstream of many important growthfactors and their receptors that have been implicated in the development and progression of HCC. In his review entitled “Targeting receptortyrosine kinase pathways in hepatocellular carcinoma”, Dr. Hung Huynh provided the latest pre-clinical and clinical developments on theefficacy of the emerging tyrosine kinase inhibitors, as well as the rationale for combination therapies for the treatment of advanced HCC.Next, an article by Dr. Jordi Muntane on “Targeting cell death and survival receptors in hepatocellular carcinoma” discussed the importanceof death receptor (DR)-mediated cell signaling in HCC, and how the most important DRs in HCC (such as TNF-R1, CD95, and TRAIL-R1and TRAIL-R2) can be targeted for enhanced therapeutic intervention. Lastly, HCC tumors have been reported to over-express the moleculartarget, ribonucleotide reductase M2 (RRM2), which is fundamentally involved in DNA synthesis. The function of RRM2 is dependent oniron, and can be competitively inhibited by gallium, which is chemically equivalent to iron. In his article “Hepatocellular carcinoma detectionby gallium scan and subsequent treatment by gallium maltolate: Rationale and case study”, Dr. Lawrence Bernstein discussed the rationale forusing an oral gallium compound, gallium maltolate, for the treatment of HCC, and presented a case study demonstrating the effectiveness ofcombining a 67Ga-scan with subsequent treatment of a patient's gallium-avid HCC.In conclusion, improved understanding of the molecular bases contributing to HCC, as well as the targets and strategies presented in thishot topic issue provide optimism for improved clinical management of HCC in the future, which will hopefully translate into prolongedpatient survival for this typically fatal malignancy. The heterogeneous pathology of HCC, evidenced by the complex interplay of multipleessential pathways underlying HCC development, suggests that rational combination therapies will likely provide synergistic anti-tumoreffects and better outcome.
Molecular Mechanisms of Liver Cancer by Hongming Pan, Xianghui Fu, Wendong Huang (493-499).
Liver cancer, hepatocellular carcinoma (HCC) in particular, is one of the most deadly cancers worldwide, and the incidence ofHCC is increasing rapidly in the United States and other developed countries. Epidemiological studies have identified major risk factorsfor HCC, including infection with hepatitis B and C virus (HBV and HCV), exposure to certain chemicals, high intake of alcohol, as wellas metabolic diseases such as obesity and diabetes that are rapidly rising in the US. Although the etiologies for liver carcinogenesis arerelatively well defined, the exact mechanism and pathways leading to cancer development are still unclear. Chronic liver injury, followedby inflammation and irregular liver regeneration has been suggested as an important step in hepatocarcinogenesis. Therefore, the identificationof key factors that protect the liver from injury and inflammation could provide valuable insight into the development of HCC. Inthis review, we will summarize the recent findings in HCC studies, mainly focusing on the new molecular link among inflammation, liverrepair and HCC.
microRNA Involvement in Hepatocellular Carcinoma by Massimo Negrini, Laura Gramantieri, Silvia Sabbioni, Carlo M. Croce (500-521).
The role of microRNAs (miRNAs) in human tumorigenesis has been demonstrated by gene profiling and functional studies.In hepatocellular carcinoma (HCC), consistently deregulated miRNAs were identified. Their aberrant expression revealed relationsshared with other types of cancer and others unique to HCC, namely the down-regulation of miR-122. Most importantly, functional andmolecular studies uncovered mechanisms that linked deregulated miRNAs to cancer-associated pathways, thereby placing their deregulationin a more rational framework. These results improved our knowledge concerning the molecular basis of HCC and helped to increaseour understanding about the great clinical potential behind these small molecules. In fact, a number of studies proved that miRNAs mayhave clinical relevance as bio-pathologic markers for HCC classification, prognostic stratification, early diagnosis or follow-up ofpatients. Additionally, the demonstration that miRNAs themselves or anti-miRNA oligonucleotides could be successfully used for in vivomodulation of miRNA actions has shown significant potentials in molecularly targeted therapy. In this context, the liver represents anorgan of election to test therapeutic possibilities associated with miRNAs.
Role of Stem Cells in Normal Liver and Cancer by Chi Keung Lau, Zhen Fan Yang, Sheung Tat Fan (522-528).
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality in the world because currenttreatments, including both surgical and non-surgical ones, cannot effectively cure this disease. Increasing evidence has revealed theimportance of cancer stem cells (CSCs) in hepatocarcinogenesis, and the idea of targeting CSCs sheds light on more effective therapeuticstrategies for HCC. In this review, normal stem cells and putative CSCs in the liver are briefly introduced. Studies about signalingpathways that regulate pathophysiological activities of liver CSCs and the therapeutic potential by targeting CSCs are also summarizedand discussed.
Role of Class II Nuclear Receptors in Liver Carcinogenesis by Guodong Li, Grace L. Guo (529-542).
Nuclear receptors (NRs) are ligand-activated transcription factors that are important to life by regulating a wide varietyof physiological and pathological functions. There are three classes of NRs defined by ligands and heterodimer partners. The Class IINRs are involved in a broad range of pathophysiological functions in the liver, including cholesterol and bile acid homeostasis; lipidand glucose metabolism; inflammation; liver regeneration and hepatocellular carcinogenesis. Due to highly complicated molecularmechanisms in the development and progression of hepatocellular carcinoma (HCC), HCC is still one of the most common malignanciesin the world. Given the pivotal functions of the Class II NRs in the liver, the roles of these NRs in hepatocellular carcinogenesis areemerging. This review summarizes the roles of Class II NRs in liver carcinogenesis and their potential application in the prevention andtreatment of HCC.
Therapeutic Potential of Targeting Glypican-3 in Hepatocellular Carcinoma by Mark Allegretta, Jorge Filmus (543-548).
Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevantbiomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation,and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studiesshow it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to the hepatocyte membraneby a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target forimmunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management ofHCC and selected other tumors that express the marker.
Points of Therapeutic Intervention Along the Wnt Signaling Pathway in Hepatocellular Carcinoma by Sarah B. Nambotin, Jack R. Wands, Miran Kim (549-559).
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. However, there is little knownabout targeted therapeutics for the treatment of this devastating tumor. Among the growth factor signaling cascades deregulated in HCC,evidences suggest that the WNT/Frizzledβmediated signaling pathway plays a key role in the hepatic carcinogenesis. Aberrant activationof the signaling in HCC is mostly due to deregulated expression of the Wnt/β-catenin signaling components. This leads to the activationof the β-catenin/TCF dependent target genes, which controls cell proliferation, cell cycle, apoptosis or motility. It has been shown thatdisruption of the Wnt/β-catenin signaling cascade displayed anti-cancer properties in HCC. Currently, no therapeutic molecules targetingthe WNT pathway are available or under clinical evaluation for the treatment of HCC. This review will discuss the identified potentialmolecular targets related to the canonical WNT signaling pathway and their potential therapeutic usefulness.
Targeting Receptor Tyrosine Kinase Pathways in Hepatocellular Carcinoma by Hung Huynh, Richard Wei Jie Ong, Peter Yi Qing Li, Swee Shean Lee, Shu Yang, Lih Wen Chong, Danh Anh Tuan Luu, Chun Tzen Jong, Irene Wei Ling Lam (560-575).
Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide with 660,000 deaths annually. Studies of themolecular pathophysiology of HCC have shown that growth factors and their corresponding receptors are commonly overexpressedand/or dysregulated in HCC. Activation of these receptors and their downstream signaling pathways can lead to angiogenesis, cell proliferation,survival and metastasis of HCC. Hence, agents that specifically block their activation and signaling cascades would be valuablefor treatment of HCC. Many small molecular tyrosine kinase inhibitors (TKIs) and antibodies have been tested in various phases of clinicaltrials. Although sorafenib has been shown to improve overall survival of patients with advanced HCC, the improvement is marginaland many patients eventually turn out to be refractory to this therapy. Thus, there is a pressing need to identify new drugs and effectivetreatments for this fatal disease. This review summarizes the pre-clinical and clinical data on the efficacy of the emerging tyrosine kinaseinhibitors as well as the rationale for combination therapies for advanced HCC treatment. Understanding the mechanisms of action ofthese therapeutic agents and methods of combining these drugs may help to increase their efficacy, reduce toxicity, and improve overallsurvival and quality of life in patients with HCC.
Targeting Cell Death and Survival Receptors in Hepatocellular Carcinoma by Jordi Muntane (576-584).
Hepatocarcinoma (HCC) is the fifth most common neoplasia in the world, and the first cause of death by cancer in some areas.The clinical course of HCC patients has improved greatly owing to the use of the oral multikinase inhibitor, Sorafenib. The expression ofreceptors belonging to the superfamily of tumor necrosis factor receptors (TNF-R), such as TNF-R1, CD95 and TNF-related apoptosisinducing ligand (TRAIL) receptor -1 (TRAIL-R1) and -2 (TRAIL-R2) are altered in patients with HCC, especially those in advancedstages of de-differentiation. The disruption of death receptor (DR)-dependent cell signaling is related to poor survival in patients withHCC. These observations, together with the lack of antitumoral therapy alternatives, have stimulated research on DR-targeted therapies.The increasing research progress in cell death shows the intense crosstalk among DR and cell survival pathways in cancer cells. Inconsequence, new potential therapeutic strategies involving antibodies or small molecules specifically targeted to DR pathways either inmonotherapy or in combination with other therapeutic strategies may be envisaged in the future to treat HCC.
Hepatocellular Carcinoma Detection by Gallium Scan and Subsequent Treatment by Gallium Maltolate: Rationale and Case Study by Lawrence R. Bernstein, Jacobus J.M. van der Hoeven, Robbert O. Boer (585-590).
Gallium is antiproliferative to many types of cancer, due primarily to its ability to act as a non-functional mimic of ferric iron(Fe3+). Because Fe3+ is needed for ribonucleotide reductase activity-and thus DNA synthesis-gallium can inhibit DNA production andcell division. Diagnostic gallium scans have shown that hepatocellular carcinoma (HCC) is commonly avid for gallium. Furthermore, invitro studies have found that gallium nitrate, and particularly gallium maltolate (GaM), have dose-dependent antiproliferative activityagainst HCC cell lines. Rationale thus exists to use GaM, an orally active compound that has been well tolerated in Phase I clinical trials,to treat patients whose HCC is gallium-avid in a gallium scan. Because gallium absorbed from orally administered GaM is bound predominatelyto serum transferrin, which travels to all tissues in the body, GaM has the potential to treat even distant metastases. A patientwith advanced HCC (20 - 10 cm primary tumor, ascites around liver and spleen, resistant to sorafenib (Nexavar®)), whose cancer washighly gallium-avid in a 67Ga-scan, was treated with oral gallium maltolate at 1500 mg/day q.d. After four weeks of treatment, the patienthad a large reduction in pain, with greatly increased mobility and quality of life, and significantly lowered serum bilirubin and inflammation-related liver enzymes. At eight weeks, CT scans showed apparent necrosis of the tumor.