Targeting the 5′-AMP-activated protein kinase and related metabolic pathways for the treatment of prostate cancer

Introduction: Increasing evidence suggests that prostate cancer cells undergo unique metabolic reprogramming during transformation. A master regulator of cellular homeostasis, 5′-AMP-activated protein kinase (AMPK), directs metabolic adaptation that supports the growth demands of rapidly dividing cancer cells. The utilization of AMPK as a therapeutic target may therefore provide an effective strategy in the treatment of prostate cancer.

Areas covered: Our review describes the regulation of AMPK by androgens and upstream kinases including the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in prostate cancer. Oncogenic, AMPK-regulated pathways that direct various metabolic processes are also addressed. Furthermore, we discuss the role of AMPK in growth arrest and autophagy as a potential survival pathway for cancer cells. In addition, by regulating non-metabolic pathways, AMPK may stimulate migration and mitosis. Finally, this review summarizes efforts to treat prostate cancer with pharmacological agents capable of modulating AMPK signaling.

Expert opinion: Current research is primarily focused on developing drugs that activate AMPK as a treatment for prostate cancer. However, oncogenic aspects of AMPK signaling calls for caution about employing such therapies. We think that inhibitors of CaMKK2 or AMPK, or perhaps the modulation of downstream targets of AMPK, will gain importance in the clinical management of prostate cancer.     

Direct AMP-activated protein kinase activators: a review of evidence from the patent literature

Introduction: AMP-activated protein kinase (AMPK), a heterotrimeric protein complex with serine/threonine kinase activity has a central role in controlling cellular energy expenditure. Small molecule-based activation of AMPK represents an attractive therapeutic proposition because of AMPK's ability to regulate several anabolic and catabolic pathways that are critical to the development of metabolic disorders and cancer.

Areas covered: A comprehensive review of published patents that disclose direct AMPK activators is provided: 26 patents comprising 10 chemical classes, and supporting in vitro and in vivo data are discussed.

Expert opinion: AMPK activation holds promise as a possible pharmacological intervention in several disease states. The development of direct, highly specific AMPK activators is necessary to fully realize the opportunities linked to AMPK activation and appreciate the risks associated with it.     

Targeting silibinin in the antiproliferative pathway

Importance of the field: Due to the failure and severe toxicity of cancer chemotherapy, silibinin, a natural flavonoid from the seeds of milk thistle, has recently received more attention for its potential anticancer and nontoxic roles in animals and humans. Silibinin has clearly demonstrated inhibition of multiple cancer cell signaling pathways, including growth inhibition, inhibition of angiogenesis, chemosensitization, and inhibition of invasion and metastasis. Cumulative evidence implicates that silibinin is a potential agent for cancer chemoprevention and chemotherapy.

Areas covered in this review: Our aim is to discuss the recent progress of silibinin in regulating multiple anticancer proliferative signaling pathways; the review covers literature mainly from the past 3 – 5 years.

What the reader will gain: One of the strategies for tumor therapy is eradication of cancer cells through targeting specific cell-proliferative pathways. This review highlights the current knowledge of silibinin in regulating multiple cellular proliferative pathways in cancer cells, including receptor tyrosine kinases, androgen receptor, STATs, NF-κB, cell cycle regulatory and apoptotic signaling pathways.

Take home message: The molecular mechanisms of silibinin-mediated antiproliferative effects are mainly via receptor tyrosine kinases, androgen receptor, STATs, NF-κB, cell cycle regulatory and apoptotic signaling pathways in various cancer cells. Targeting inhibition of proliferative pathways through silibinin treatment may provide a new approach for improving chemopreventive and chemotherapeutic effects.     

Targeting of AMP-activated protein kinase: prospects for computer-aided drug design

Introduction: Dysregulation of energy homeostasis has been implicated in a number of human chronic diseases including diabetes, obesity, cancer, and inflammation. Given the functional attributes as a central regulator of energy homeostasis, AMP-activated protein kinase (AMPK) is emerging as a therapeutic target for these diseases, and lines of evidence have highlighted the need for rational and robust screening systems for identifying specific AMPK modulators with a therapeutic potential for preventing and/or curing these diseases.

Areas covered: Here, the authors review the recent advances in the understanding of three-dimensional structures of AMPK in relationship with the regulatory mechanisms, potentials of AMPK as a therapeutic target in human chronic diseases, and prospects of computer-based drug design for AMPK.

Expert opinion: Accumulating information of AMPK structure has provided us with deep insight into the molecular basis underlying the regulatory mechanisms, and further discloses several structural domains, which can be served for a target site for computer-based drug design. Molecular docking and simulations provides useful information about the binding sites between potent drugs and AMPK as well as a rational screening format to discover isoform-specific AMPK modulators. For these reasons, the authors suggest that computer-aided virtual screening methods hold promise as a rational approach for discovering more specific AMPK modulators.     

Silibinin: a potential old drug for cancer therapy

Introduction: Silibinin is mixture of flavonolignans extracted from milk thistle and often has been used in the treatment of acute and chronic liver disorders caused by toxins, drug, alcohol and hepatitis and gall bladder disorders for its antioxidant and hepatoprotective properties.

Areas covered: However, increasing evidence suggest that silibinin is not solely limited in the treatment of these diseases. Further research suggests that silymarin may function diversely and may serve as a novel therapy for cancer therapy, such as lung cancer, prostatic cancer, colon cancer, breast cancer, bladder cancer and hepatocellular carcinoma by regulating cancer cells growth, proliferation, apoptosis, angiogenesis and many other mechanism.

Expert commentary: In this review, in order to provide potential new treatment for these cancer, we summarize the recent anti-cancer findings of silibinin in these cancer and clarify the mechanisms of this effect.     

Screening methods for AMP-activated protein kinase modulators: a patent review

Introduction: AMP-activated protein kinase (AMPK) functions as a cellular energy gauge that maintains cellular homeostasis and has been suggested to play important roles in tumorigenesis, lifespan and autophagy. Accordingly, AMPK is a potential target of drugs for controlling a growing number of human diseases ranging from metabolic disorders to cancer, highlighting the need for rational and robust screening systems for identifying compounds that modulate AMPK.

Areas covered: The relevant screening methods in the patent and scientific literature were analyzed, and key features of direct AMPK modulators are discussed in the context of their physiological relevance and the three-dimensional structure of the AMPK complex.

Expert opinion: The mechanism of action of modulators is important in designing drugs with enhanced efficacy, specificity and stability. Most patented assay formats for identifying AMPK modulators are based on classical enzyme assays that monitor AMPK activity or changes in AMPK-dependent cellular physiology. However, these systems do not provide information about underlying mechanisms. Two patented assay systems use a specific domain or the three-dimensional structure of AMPK to identify AMPK modulators. The recent identification of two AMPK modulators, A-769662 and C-2 (or its prodrug, C-13), suggests the promise of structure-based assays in discovering more potent and specific modulators of AMPK.     

Involvement of long non-coding RNA HULC (highly up-regulated in liver cancer) in pathogenesis and implications for therapeutic intervention

Introduction: HULC (highly upregulated in liver cancer) is a long non-coding RNA (lncRNA) which is, as its name suggests, highly upregulated in hepatocellular carcinoma and in several other cancers. Increased HULC expression levels are strongly associated with clinicopathologic features such as tumor stages and overall survival and is a driver of tumor proliferation, migration, and invasion.

Areas covered: This review addresses the discovery of HULC and discusses the consequences of HULC deregulation in cancer, the underlying molecular mechanisms and the potential of HULC as a biomarker and therapeutic target.

Expert opinion: HULC is a promising candidate as a therapeutic target in cancer; however, more studies are necessary to further elucidate the underlying molecular mechanism(s), especially in cancer types other than hepatocellular carcinomas. Future studies that focus on an optimized HULC-targeting approach are necessary to clarify the best strategy to target this lncRNA in vivo and in patients.     

Therapeutic targeting of B7-H1 in breast cancer

Introduction: Breast cancer is the most common form of malignancy occurring in women worldwide. B7-H1 is a co-inhibitory molecule expressed by several types of tumors, including breast cancer. The aberrant expression of B7-H1 in breast cancer cells has been determined, its role in recruiting regulatory T cells into the tumor microenvironment has been elucidated and a strong link to B7-H1 induction in highly proliferative breast cancer has been provided. It has also been demonstrated that doxorubicin, a drug commonly used for breast cancer treatment, downregulates the cell surface expression of B7-H1 and upregulates its nuclear expression, which therefore suggests an anti-apoptotic role of B7-H1 in breast cancer.

Areas covered: This review illustrates the various factors involved in the induction of B7-H1 and its role in immune evasion and chemoresistance. It also provides potential therapeutic strategies for targeting B7-H1 in breast cancer.

Expert opinion: B7-H1 should be considered as a potential therapeutic target for breast cancer. Indeed, there is increasing evidence for the potential efficacy of B7-H1 blockade in the prevention of immune evasion by cancer cells. Additionally, B7-H1 targeting can be used in conjunction with other therapeutic modalities for improved efficacy and reduced toxicity. We expect that B7-H1 blockade in combination with other therapeutics will be a prime therapeutic strategy in the future.     

Targeting AAC-11 in cancer therapy

Importance of the field: Since its discovery in 1997, the antiapoptotic factor AAC-11 has rapidly gained attention due to its potential use in cancer therapy. Indeed, most cancer cells express elevated levels of AAC-11, which is now known to be involved in both tumor cells growth as well as sensitivity to chemotherapeutic drugs.

Areas covered in this review: In this review, we examine the most recent evidence about the role of AAC-11 in cancer biology and the therapeutic perspectives associated with its specific targeting. For that purpose, literature dealing with AAC-11 in the PubMed database was reviewed from 1997 up to date.

What the reader will gain: AAC-11 is an antiapoptotic gene that has the potential to be a target for anti-cancer therapy, and warrants further investigation. As its expression seems to predict unfavorable prognosis, at least in some cancers, it also may become a potent prognostic marker.

Take home message: Blocking AAC-11 function in cancer for therapeutic purposes might be of great interest. The recent report of efficient AAC-11 inhibiting peptides that sensitize tumor cells to chemotherapeutic drugs has raise the exciting notion that AAC-11 might be a druggable target and fueled the search for new therapeutic agents that could block AAC-11 function.     

RhoGDI2 as a therapeutic target in cancer

Importance of the field: Rho GDP dissociation inhibitor 2 (RhoGDI2) has been identified as a regulator of Rho GTPases that play important roles in the development of numerous aspects of the malignant phenotype, including cell cycle progression, resistance to apoptotic stimuli, neovascularization, tumor cell motility, invasiveness, and metastasis. Although RhoGDI2 has been known to be expressed only in hematopoietic tissues, recent studies suggest that this protein is also aberrantly expressed in several human cancers and contributes to aggressive phenotypes, such as invasion and metastasis. Hence, RhoGDI2 appears to be a target of interest for therapeutic manipulation.

Areas covered in this review: Here, we summarize the role of RhoGDI2 in human cancers, specifically metastasis-related processes, and discuss its potential as a therapeutic target.

What the reader will gain: RhoGDI2 modulates the invasiveness and metastatic ability of cancer cells through regulation of Rac1 activity.

Take home message: RhoGDI2 may be a useful marker for tumor progression in human cancers, and interruption of the RhoGDI2-mediated cancer cell invasion and metastasis by an interfacial inhibitor may be a powerful therapeutic approach to cancer.     

Reversal and Inhibition of ADP-Ribosylation (A-R) of GTP-Binding Proteins Catalysed by Bacterial Toxins

Introduction: Cancer initiation and propagation is not possible without cell division. Besides microtubules, which are targeted by taxanes as part of a number of standard chemotherapy regimens, mitosis depends on small cellular organelles known as centrosomes. Centrosome abnormalities are a common finding in tumors including major human malignancies such as prostate or breast cancer. Centrosome aberrations can drive chromosome missegregation and aneuploidy, thereby promoting malignant progression. Nonetheless, these important cellular structures have not yet been directly exploited for targeted interventions.

Areas covered: This review will summarize the current knowledge of normal and aberrant centrosome duplication. We will highlight the principal pathways leading to aberrant centrosome numbers and the evidence for a role of centrosome amplification in malignant progression. Strategies to target centrosome-mediated cell division errors will be discussed. Lastly, we will review the evidence for centrosome clustering as a druggable cellular process.

Expert opinion: Recent advances in the understanding of centrosome biogenesis have revealed a number of potential centrosomal drug targets including Polo-like kinases, Cyclin-dependent kinases, Aurora kinases, and molecular motor proteins. For some of these proteins, targeted inhibitory compounds are available and in vitro experiments have provided the proof-of-concept that blocking centrosome overduplication can result in a reduction of aneuploid cells. In addition, inhibition of centrosomal clustering has antitumor activity in vitro and in vivo. Nonetheless, further in vitro and preclinical studies are required to determine the most effective way to exploit the centrosome for therapeutic or preventive anticancer strategies.     

Adrenomedullin as a therapeutic target in angiogenesis

Importance of the field: Hypoxia, a frequent characteristic in the microenvironment of solid tumors, leads to adrenomedullin (AM) upregulation through the hypoxia inducible factor-1 pathway, explaining its high expression in a variety of malignant tissues. AM is believed to play an important role in tumor progression and angiogenesis in many cancers. Therefore, it could become a new therapeutic target.

Areas covered in this review: We performed a review of the literature based on published data to highlight AM's critical roles in tumor cell growth and cancer invasiveness, and its involvement in tumor angiogenesis through promotion of recruitment of hematopoietic progenitors, vascular morphogenesis, and blood vessel stabilization and maturation. Inhibition of AM has antitumoral effects linked to antiangiogenic effects but in some cases also to direct antiproliferative activity on cancer cells. Several studies demonstrated that systemic inhibition of AM receptors was well tolerated in murine models.

What the reader will gain: The goal of this review is to inform readers about the role of AM in tumor angiogenesis and cancer progression and, therefore, about its possible place as a new therapeutic target.

Take home message: Taken together, these data support targeting the AM pathway as a new potential therapy in cancer, complementary to other existing treatments.     

14-3-3ζ as a prognostic marker and therapeutic target for cancer

Importance of the field: The ubiquitously expressed 14-3-3ζ protein is involved in numerous important cellular pathways involved in cancer. Recent research suggests 14-3-3ζ may play a central role regulating multiple pathways responsible for cancer initiation and progression. This review will provide an overview of 14-3-3 proteins and address the role of 14-3-3ζ overexpression in cancer.

Areas covered in this review: The review covers the basic role of 14-3-3 in regulation of multiple pathways with a focus on 14-3-3ζ as a clinically relevant biomarker for cancer recurrence.

What the reader will gain: 14-3-3ζ overexpression has been found in multiple cancers; however, the clinical implications were unclear. Recently, 14-3-3ζ has been identified as a biomarker for poor prognosis and chemoresistance in multiple tumor types, indicating a potential clinical application for using 14-3-3ζ in selecting treatment options and predicting cancer patients' outcome.

Take home message: 14-3-3ζ is a potential prognostic marker of cancer recurrence and predictive marker for therapeutic resistance. The overexpression of 14-3-3ζ in multiple cancers suggests that it may be a common target to intervene tumor progression; therefore, more efforts are needed for the development of 14-3-3 inhibitors.     

Therapeutic application of vitamin D receptor ligands: an updated patent review

Introduction: The vitamin D receptor (VDR) is a promising drug target in the treatment of cancer, autoimmune disease, inflammation, infection and cardiovascular disease, as well as bone and mineral disorders. Although many VDR ligands have been developed and shown to activate VDR in vitro and in vivo, including vitamin D derivatives and non-secosteroidal compounds, a principal adverse effect of hypercalcemia has limited their clinical application.

Areas covered: We summarize recent patent activity regarding VDR ligands, including vitamin D derivatives, non-secosteroidal compounds and tissue-selective prodrugs, alongside their therapeutic applications. The potential for use of VDR ligands in the treatment of hepatic fibrosis, pancreatic fibrosis and neuronal disease is also reviewed.

Expert opinion: Several VDR ligands have been shown to have increased therapeutic efficiency in experimental models of cancer, inflammation and cardiovascular disease, and to exhibit function-selective and/or tissue-selective activity. The underlying molecular and pharmacological mechanisms remain to be elucidated. Further studies, both basic and applied, should make successful VDR-targeting therapy possible.     

Therapeutic targeting of the p53 pathway in cancer stem cells

Introduction: Cancer stem cells (CSCs) are a high profile drug target for cancer therapeutics due to their indispensable role in cancer progression, maintenance and therapeutic resistance. Restoring wild-type (WT) p53 function is an attractive new therapeutic approach for the treatment of cancer due to the well-described powerful tumor suppressor function of p53. As emerging evidence intimately links p53 and stem cell biology, this approach also provides an opportunity to target CSCs.

Areas covered: This review covers the therapeutic approaches to restore the function of WT p53, cancer and normal stem cell biology in relation to p53 and the downstream effects of p53 on CSCs.

Expert opinion: The restoration of WT p53 function by targeting p53 directly, its interacting proteins or its family members holds promise as a new class of cancer therapies. This review examines the impact that such therapies may have on normal and CSCs based on the current evidence linking p53 signaling with these populations.     

Treatment options for esophageal squamous cell carcinoma

Introduction: The treatment for esophageal squamous cell carcinoma (SCC) depends on its etiology. For mucosal cancer, endoscopic resection is standard; while for locally advanced cancer, esophagectomy is the main treatment. When the tumor is more advanced, neoadjuvant or adjuvant therapy is added. For unresectable cancer, concurrent chemoradiotherapy is the standard therapy.

Areas covered: The standard chemotherapy for esophageal SCC is a cisplatin- and 5-fluorouracil (CF)-based regimen. Chemoradiotherapy (CRT) is the standard treatment for unresectable esophageal SCC and is also an option for resectable tumors. For patients who are inoperable, concurrent CRT should be the standard of care. Docetaxel, cisplatin and 5-fluorouracil (DCF) therapy is a promising candidate for chemotherapy with or without radiotherapy because an excellent local control rate and pathological remission rate have been reported. Although salvage surgery after definitive CRT is a practical treatment, judicious patient selection is crucial.

Expert opinion: Presently, the standard regimen for esophageal SCC is CF. DCF is expected to be the next standard regimen. In the near future, some new therapeutic options, such as molecular targeted therapy or particle beam therapy, may confer further advantages. A thorough understanding of these therapeutic modalities is important to achieve this endeavor.