Current Cancer Drug Targets - Volume 12, Issue 9, 2012

Hepatocellular carcinoma (HCC) is a global health problem and responsible for up to 500.000 deaths annually. It usually occurs secondary to infections with hepatitis B or C viruses, alcohol consumption, non-alcoholic steatohepatitis or hereditary liver diseases. The prognosis for patients with advanced disease is dismal; therefore, new strategies to prevent or treat this malignancy are urgently needed. Over recent years, several molecular pathways have been identified contributing to the molecular pathogenesis of this devastating disease, among them the PI3K/AKT/mTOR pathway. mTOR is effectively inhibited by rapamycin and its derivatives such as temsirolimus and everolimus. The anti-tumor activity of rapamycin was identified more than 30 years ago in a screen performed at the National Cancer Institute, but was subsequently not developed for cancer treatment. In the 1990s, activation of the mTOR pathway was recognized in various malignancies spurring again the interest in mTOR inhibitors for anti-cancer treatment. In 2007, the US Food and Drug Administration approved the first mTOR inhibitor, temsirolimus, for the treatment of renal cell carcinoma. Currently, several clinical studies are underway to define the role of mTOR inhibitors for the treatment of hepatocellular carcinoma. The aim of this review is to outline the role of mTOR for hepatocarcinogenesis. We will also discuss the latest preclinical and clinical data of mTOR inhibitors for the prevention and treatment of HCC.

In May 2007, sorafenib (Nexavar®) was approved for “unresectable hepatocellular carcinoma (HCC)”, and was the first molecular targeted agent for use in HCC. To date, sorafenib is the only molecular-targeted agent, whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and has now been approved worldwide. Phase III clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are now ongoing. Phase III clinical trials of several targeted agents comparing them with placebo as second-line treatment agents for patients who failed or was intolerable to sorafenib are also ongoing. In addition, combination of sorafenib with standard treatment such as resection, ablation, transarterial chemoembolization, and hepatic arterial infusion chemotherapy are ongoing.This review outlines the clinical utility of sorafenib in the treatment algorithm of HCC. Furthermore, it also reviews the current status of clinical trials of new agents or combination therapy with sorafenib and standard treatment. Finally, further prospect of the paradigm shift of the HCC treatment is also discussed.

Hepatocellular carcinoma (HCC) is a common malignancy that affects a large number of patients worldwide, with an increasing incidence in the United States and Europe. The therapies that are currently available for patients with inoperable HCC have limited benefits. Although molecular targeted therapies against selected cell signaling pathways have shown some promising results, their impact has been minimal. There is a need to identify and explore other targets for the development of novel therapeutics. Several non-protein coding RNAs (ncRNA) have recently been implicated in hepatocarcinogenesis and tumor progression. These ncRNA genes represent promising targets for cancer. However, therapeutic targeting of ncRNA genes has not been employed for HCC. The use of antisense oligonucleotides and viral vector delivery approaches have been shown to be feasible approaches to modulate ncRNA expression. HCC is an optimal cancer to evaluate novel RNA based therapeutic approaches because of the potential of effective delivery and uptake of therapeutic agents to the liver. In this review, we discuss selected ncRNA that could function as potential targets in HCC treatment and outline approaches to target ncRNA expression. Future challenges include the need to achieve site-specific targeting with acceptable safety and efficacy.

Hepatocellular carcinoma (HCC) is one of the most common human cancers. HCC is a chemoresistant cancer and the current drug therapy has limited efficacy. As a result, the prognosis of HCC patients is generally poor. Recent studies have demonstrated that a subpopulation of cancer cells with stem cell properties, called cancer stem cells (CSCs), are responsible for growth and metastasis of cancer. CSCs characterized by several markers including CD133, CD44, CD90, OV6, Epithelial cell adhesion molecule (EpCAM) and CD13 have been isolated from different human HCC cell lines or specimens. CSCs share many of the signaling pathways found in normal stem cells, such as Wnt, Hedgehog, Notch and Transforming growth factor-beta (TGF-β) pathways. These pathways are involved in self-renewal, differentiation and survival of CSCs. There is evidence of deregulation of these pathways in HCC CSCs. MicroRNAs also play an important role in regulating signaling pathways in HCC, and recent data suggested an important role of microRNA in CSCs of HCC. Therapeutic targeting of CSCs may provide a novel strategy that is more effective than the current drugs targeting the bulk mature cancer cells in treatment of HCC.

Hepatocellular carcinoma (HCC) remains one of the most lethal cancers in the world. Since current treatment options including surgical resection and liver transplantation offer limited therapeutic benefits, there exists a need to evaluate novel therapeutic strategies for the amelioration of HCC. Hepatic tumors are highly vascularized, possessing a rich network of blood vessels and capillaries and there exist an angiogenic component to the tumor growth observed in HCC. Thus, anti-angiogenic therapy has been suggested to possess tremendous therapeutic potential in the treatment of HCC. The process of angiogenesis involves multiple biochemical checkpoints and signaling steps, and thus providing a multitude of opportunities for therapeutic intervention. In this review, we highlight the role of angiogenesis and its use as a therapeutic strategy for HCC. The first part of the article reviews the angiogenic mechanisms with particular emphasis on the multitude of biochemical factors, such as receptors, enzymes and cytokines involved in the complex interplay of new capillary growth. Next, we present the pre-clinical studies which elucidate the anti-angiogenic effects of both dietary and non-dietary agents in animal models of HCC. Of particular interest is the examination of the effects of the antiangiogenic agents on the various angiogenic markers in the hepatic tissue of the animal challenged either with a hepatocarcinogen or xenografted with hepatic neoplastic cells. The review also highlights the clinical investigations carried out in HCC patients to evaluate the therapeutic potential of pharmacological agents with proven anti-angiogenic properties. Finally, the future directions as well as the benefits and potential challenges involved in the use of antiangiogenic pharmacotherapy in the treatment of HCC are also discussed.

The poor prognosis for hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, development of effective strategies for preventing recurrence and secondary tumors will improve the clinical outcome of HCC patients. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway is profoundly associated with liver carcinogenesis, and thus, may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), which inhibits Ras-MAPK activation and RXRα phosphorylation, successfully prevents HCC recurrence, thus improving patient survival. The fundamental concept of HCC chemoprevention by ACR is “clonal deletion,” which is defined as the removal of latent malignant clones from the liver before they expand into clinically detectable HCC. “Combination chemoprevention” using ACR as a key drug holds great promise of a new effective strategy for the prevention of HCC because of its synergism. ACR is also expected to prevent the development of HCC in obese people, who are at an increased risk to HCC, because this agent significantly inhibits obesity-related liver tumorigenesis in the rodent model. Here, we review the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research.

Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice.

In this review, the role of nuclear factor-κB (NF-κB) in hepatocarcinogenesis is examined. The administration of several hepatic tumor promoters leads to the activation of NF-κB in the liver of rats and mice. Many studies support the hypothesis that the activation of NF-κB in the liver is inhibited by antioxidants. The role of NF-κB in hepatocarcinogenesis has been examined using NF-κB overexpression and knockout models. The role of NF-κB in liver carcinogenesis is complex; some models show that NF-κB contributes to carcinogenesis whereas others see no effect or an inhibition. Overall, although hepatic tumor promoting agents can activate NF-κB and this activation can be inhibited by antioxidants, the significance of this activation is unclear.

Bioactive food components (BFACs) represent promising candidates for liver cancer chemoprevention. Among them, isoprenic derivatives (carotenoids, retinoids, perillyl alcohol, limonene, geraniol, farnesol, geranylgeraniol and β- ionone) can be highlighted. The relevance of animal models for the investigation of chemopreventive agents is supported by comparative functional genomic studies that reinforce the similarities between rodent and human hepatocarcinogenesis. Thus, characterization of BFACs in animal models as blocking and/or suppressing agents allows the establishment of the theoretical basis for the development of chemoprevention strategies. Dietary isoprenic derivatives actions on hepatocarcinogenesis may involve a block in carcinogen activation, induction of phase 2 enzymes and an antioxidant activity, as well as interference with cellular processes including cell communication, proliferation, apoptosis, differentiation and remodeling of preneoplastic lesions. Dietary isoprenic derivatives modulate molecular targets including HMG-CoA-reductase, Rho, nuclear receptors, c-myc, connexin 43, NF-κB and Nrf2. Several networks related to these targets are altered in early phases of hepatocarcinogenesis. This emphasizes the importance of such agents for the chemoprevention of hepatocellular carcinoma. Combinations of isoprenic derivatives or of these substances with other BFACs classes should be further investigated. Also, toxicity and bioavailability and pharmacokinetic aspects of these derivatives represent relevant issues in their development as chemopreventive agents. One major current limitation of the adoption of dietary isoprenic derivatives for liver cancer chemoprevention is the challenge in overcoming the initial preclinical phase in agent development. Dietary isoprenic derivatives that present liver cancer chemopreventive properties should be further explored in clinical trials, begining with the phase 0 approach.

Hepatocellular carcinoma (HCC), one of the most common and lethal cancers, is a growing menace in modern society. Until recently, the majority of detected cases of liver cancer have been found in the developing nations of Asia and Africa; however, its occurrence has significantly increased in the United States. HCC occurs due to several etiologies, such as alcoholism, dietary carcinogens, iron overload, viral hepatitis, as well as several hepatic chronic diseases. In view of the limited treatment options, such as surgery and transplantation, a critical need exists to examine alternative approaches. The use of phytochemicals obtained from dietary sources provides a novel and fascinating preventive and therapeutic approach against HCC. Dietary phytochemicals possess potent antioxidant and anti-inflammatory properties which are extremely critical to combat the significant oxidative stress and inflammation implicated in liver cancer. An impressive number of phytochemicals have shown considerable promise as candidates for the prevention and treatment of HCC. In this article, we systematically review the in vivo pre-clinical evidence documenting the chemopreventive and therapeutic potential of several important dietary phytochemicals in HCC. This review critically examines the molecular mechanisms of the pharmacological effects of the aforementioned animal studies. Clinical and epidemiological studies are also highlighted in this review. Emerging issues such as bioavailability, dose optimization, targeted drug delivery, role of botanical extracts and synergy are also discussed. Finally, current challenges, limitations, future directions, innovative concepts and novel hypotheses for the use of dietary phytochemicals in the chemoprevention and amelioration of human HCC are presented.

Hepatocellular carcinoma (HCC) is considered as auxotrophic for arginine and BCT-100, a new recombinant human arginase, has been synthesized for arginine deprivation to inhibit arginine-dependent tumor growth. The aim of the present study was to evaluate the effects of BCT-100 on the inhibition of in vitro cell proliferation of HCC cell lines and in vivo tumor growth. The molecular mechanism involved was also studied. The anti-tumor efficacy of BCT-100 on cell proliferation, cell cycle distribution and cellular apoptosis were determined in human hepatoma HepG2 and PLC/PRF/5 cells. Protein expression in the Wnt/β-catenin and Akt signaling pathways were analyzed by western blotting. Tumors were also established subcutaneously and BCT-100, in combination with oxaliplatin, was administrated i.p. to study the anti-tumor growth of the drugs. Treatment with BCT-100 was found to inhibit cell proliferation and enhance caspasedependent cellular apoptosis. Cell cycle arrest at S phase was observed. Inhibition of Wnt/β-catenin and Akt signaling pathways, with a reduction in survivin and XIAP protein expressions, were also observed. Furthermore, combined treatment of BCT-100 and chemotherapy with oxaliplatin demonstrated synergistic inhibiting effect on tumor growth and the overall survival probability was enhanced as compared with BCT-100 or oxaliplatin treatment alone. These preclinical data demonstrate robust anti-tumor activity of BCT100 in HCC, thus providing the basis for its exploitation as a potential therapeutic agent in arginine-driven tumors. The positive effect of testing BCT100 with oxaliplatin in PLC/PRF/5 tumours also supports the rationale of combining BCT-100 and oxaliplatin in the clinical treatment of HCC.

Hepatocellular carcinoma (HCC), considered to be one of the most lethal cancers with almost >1 million deaths reported annually worldwide, remains a devastating disease with no known effective cure. Hence, chemopreventive strategies come into play, offering an effective and safe mode of treatment, ideal to ward off potential cancer risks and mortality. A major predisposing condition, pertinent to the development and progression of HCC is oxidative stress. We previously reported a striking chemopreventive effect of anthocyanin-rich black currant skin extract (BCSE) against diethylnitrosamine (DENA)-initiated hepatocarcinogenesis in rats. The current study aims to elucidate the underlying antioxidant mechanisms of black currant anthocyanins implicated in the previously observed chemopreventive effects against experimental hepatocarcinogenesis. Dietary BCSE (100 and 500 mg/kg) administered four weeks before and 18 weeks after DENA challenge decreased abnormal lipid peroxidation, protein oxidation, and expression of inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in a dose-responsive fashion. Mechanistic studies revealed that BCSE upregulated the gene expression of a number of hepatic antioxidant and carcinogen detoxifying enzymes, such as NAD(P)H:quinone oxidoreductase, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase isoenzymes, in DENA-initiated animals. Protein and mRNA expressions of nuclear factor E2-related factor 2 (Nrf2) were substantially elevated with BCSE treatment, providing a direct evidence of a coordinated activation of the Nrf2-regulated antioxidant pathway, which led to the upregulation of a variety of housekeeping genes. The results of our study provide substantial evidence that black currant bioactive anthocyanins exert chemopreventive actions against DENA-inflicted hepatocarcinogenesis by attenuating oxidative stress through activation of Nrf2 signaling pathway.