Cardiac glycosides as novel cancer therapeutic agents

The class of steroid-like compounds designated cardiac glycosides includes well-known drugs such as digoxin, digitoxin, and ouabain. Their continued efficacy in treatment of congestive heart failure and as anti-arrhythmic agents is well appreciated. Less well known, however, is the emerging role of this category of compounds in the prevention and/or treatment of proliferative diseases such as cancer. New findings within the past five years have revealed these compounds to be involved in complex cell-signal transduction mechanisms, resulting in selective control of human tumor but not normal cellular proliferation. As such, they represent a promising form of targeted cancer chemotherapy. New clinical studies of their anticancer potential as single or adjuvant treatments may provide insight into these potentially valuable therapeutic options. This review focuses on recent findings on cellular pharmacology of cardiac glycosides as they relate to treatment of human cancer and attempts to explain why these agents have been overlooked in the past.     

Emerging therapeutic approaches for osteogenesis imperfecta

Osteogenesis imperfecta (OI) is an incurable genetic brittle-bone disease. Although drug therapy, surgery and physiotherapy represent current treatments for OI, the search is ongoing for effective and innovative new therapies targeting the underlying causes of the disease. In this regard, recent advances in the fields of gene and stem-cell therapies have been considerable. In spite of the many challenges that remain, potential new therapies for OI, which have been tested in cell culture systems, animal models and patients, offer hope for the future development of successful therapies. Recent progress in the field is reviewed here.     

Promising therapeutic agents for sepsis

The incidence of sepsis is expected to increase at a rate of 1.5% per year. Advances in our understanding of the sepsis syndrome have enabled researchers to identify new therapeutic targets and design therapies for existing mediators of sepsis. Drotrecogin alfa (activated) was the first biological treatment for serious sepsis approved by the Food and Drug Administration in 2001. There have also been promising research results involving ethyl pyruvate, glycogen synthase kinase-3 inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Here, we review these four compounds and compound classes as examples of emerging pharmacological treatments of severe sepsis and describe the current status of sepsis research.     

Novel racemosin B derivatives as new therapeutic agents for aggressive breast cancer

Carbazole derivatives show anti-cancer activity and are of great interest for drug development. In this study, we synthesized and analyzed several new alkylamide derivatives of racemocin B, a natural indolo[3,2-a]carbazole molecule originally isolated from the green alga Caulerpa racemose. Several alkylamide derivatives were found to exhibit moderate to strong growth inhibition against human breast cancer cell lines. They induced G2/M cell cycle arrest and apoptosis in the aggressive triple-negative breast cancer cell line MDA-MB-231. Among these derivatives, compound 25 with the lowest IC₅₀ induced cell death by suppressing autophagy. This was accompanied by inhibition of autophagic flux and accumulation of autophagy protein 1 light chain 3, LC3II, and p62. The novel alkylamide derivative offers a potential new treatment for human breast cancer.     

Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.     

Identification of a series of tetrahydroisoquinoline derivatives as potential therapeutic agents for breast cancer

A series of tetrahydroisoquinoline-N-phenylamide derivatives were designed, synthesized, and tested for their relative binding affinities, and antagonistic activities against estrogen receptor (ER). Compound 1f (relative binding affinity, RBA=5) showed higher binding affinity than tamoxifen (RBA=1), a potent ER antagonist and currently being used for breast cancer therapy. Compound 1f also exerted optimal antagonistic activity against ER in reporter and cell proliferation assays. Interestingly, compound 1j, which only has a minor agonistic effect against ER, acted as a progesterone receptor (PR) antagonist and exerted agonistic activity against AP-1 through ER pathway. Our results show that these new compounds can be employed as leading pharmacophore for further development of potent selective ER and/or PR modulators or antagonists.     

Emerging roles for cancer registries in cancer control

Cancer registries are a vital part of the national cancer effort to cut United States cancer mortality rates in half by the year 2000. Registries provide the data to focus programs and monitor progress. Success in meeting the year 2000 goal will require aggressive attention to the opportunities for prevention, early detection, treatment, and applied cancer control research, all of which complement the current emphasis on basic research.     

Novel therapeutic agents for cutaneous T-Cell lymphoma

Mycosis fungoides (MF) and Sezary Syndrome (SS) represent the most common subtypes of primary Cutaneous T-cell lymphoma (CTCL). Patients with advanced MF and SS have a poor prognosis leading to an interest in the development of new therapies with targeted mechanisms of action and acceptable safety profiles. In this review we focus on such novel strategies that have changed the treatment paradigm of this rare malignancy.     

Carbohydrate-binding proteins in cancer, and their ligands as therapeutic agents

Experimental evidence directly implicates complex carbohydrates in recognition processes, including adhesion between cells, adhesion of cells to the extracellular matrix, and specific recognition of cells by one another. In addition, carbohydrates are recognized as differentiation markers and as antigenic determinants. Lectins are nonenzymatic proteins present in plants and animals, which preferentially bind to specific carbohydrate structures and play an important role in cell recognition. Modified carbohydrates and oligosaccharides have the ability to interfere with carbohydrate-protein interactions and therefore, inhibit the cell-cell recognition and adhesion processes, which play an important role in cancer growth and progression. Carbohydrate ligands therefore, are candidates to play important roles in cancer therapeutics.     

Emerging pharmacologic therapies for prostate cancer

The last decade has seen explosive growth in the therapy of prostate cancer. Three areas of therapeutics are emerging: 1) new compounds with novel uses; 2) available compounds with new applications; and 3) new compounds applied to established indications. The novel compounds target specific receptor sites of cancer pathways and attack cancer cells with less effect on normal tissue. Earlyphase trials with compounds targeting the endothelin-A and EGF receptors have shown encouraging results in hormone-refractory prostate cancer. In addition, the Early Prostate Cancer Trial of over 8000 men is currently underway to determine the benefit of adjuvant androgen ablation with bicalutamide in men with localized prostate cancer. Early results show a significant 42% reduction in the progression of the disease in the bicalutamide treatment arm. Further, in large, phase 3 clinical trials in patients needing androgen ablation, the GnRH antagonist abarelix caused no testosterone surge and demonstrated a significantly more rapid decline in serum testosterone to the castrate level than did an LHRH agonist analogue. Abarelix should thus have application as a monotherapy in patients who need a rapid onset of action or are at high risk of complications from the clinical flare seen with LHRH agonists. Abarelix also uniquely caused a sustained decline in serum FSH levels, which have been shown in vitro to stimulate prostate cancer cell growth. If these favorable effects can be duplicated in patients, abarelix might also offer a survival benefit.     

Emerging role of LETM1/GRP78 axis in lung cancer

The selective autophagy of damaged mitochondria is called mitophagy. Mitochondrial dysfunction, mitophagy, and apoptosis have been suggested to be interrelated in various human lung carcinomas. Leucine zipper EF-hand-containing transmembrane protein-1 (LETM1) was cloned in an attempt to identify candidate genes for Wolf–Hirschhorn syndrome. LETM1 plays a role in mitochondrial morphology, ion homeostasis, and cell viability. LETM1 has also been shown to be overexpressed in different human cancer tissues, including lung cancer. In the current study, we have provided clear evidence that LETM1 acts as an anchoring protein for the mitochondria-associated ER membrane (MAM). Fragmented mitochondria have been found in lung cancer cells with LETM1 overexpression. In addition, a reduction of mitochondrial membrane potential and significant accumulation of microtubule-associated protein 1 A/1B-light chain 3 punctate, which localizes with Red-Mito, was found in LETM1-overexpressed cells, suggesting that mitophagy is upregulated in these cells. Interestingly, glucose-regulated protein 78 kDa (GRP78; an ER chaperon protein) and glucose-regulated protein 75 kDa (GRP75) were posited to interact with LETM1 in the immunoprecipitated LETM1 of H460 cells. This interaction was enhanced in cells treated with carbonyl cyanide m-chlorophenylhydrazone, a chemical mitophagy inducer. Treatment of cells with honokiol (a GRP78 inhibitor) blocked LETM1-mediated mitophagy, and CRISPR/Cas9-mediated GRP75 knockout inhibited LETM1-induced autophagy. Thus, GRP78 interacts with LETM1. Taken together, these observations support the notion that the complex formation of LETM1/GRP75/GRP78 might be an important step in MAM formation and mitophagy, thus regulating mitochondrial quality control in lung cancer.Subject terms: Non-small-cell lung cancer, Mitophagy     

Intrabodies as therapeutic agents

In the past decade, a large number of intracellular antibodies (intrabodies) have been developed for potential use as therapeutic agents. As antibodies can be generated against virtually any target antigen, the applications of intrabodies span a wide range including tumour therapy, infectious diseases, transplantation, and other diseases associated with protein overexpression or mutagenesis. This article summarises the development of intrabodies and their applications as therapeutic agents.     

Gold compounds as therapeutic agents for human diseases

The application of gold in medicine is traceable for several thousand years and Au(i) compounds have been used clinically to treat rheumatoid arthritis since the last century. Recently research into gold-based drugs for a range of human diseases has seen a renaissance. Old as well as new Au(i) and Au(iii) compounds have been used and designed with an aim of targeting cellular components that are implicated in the onset or progression of cancers, rheumatoid arthiritis, viral and parasitic diseases. In addition, new disease targets have been found for gold compounds that have given insight into the mechanism of action of these compounds, as well as in the molecular pathophysiology of human diseases. Here we discuss the rationale for the design and use of gold compounds that have specific and selective targets in cells to alleviate the symptoms of a range of human diseases. We summarise the most recent findings in this research and our own discoveries to show that gold compounds can be developed to become versatile and powerful drugs for diseases caused by dysfunction of selenol and thiol containing proteins.     

State-of-the-art therapeutic medical countermeasures for viral threat agents

In recent years, there has been an increase in the perceived threat of biological agents being used against civilian populations. This has prompted an urgent need for the development and procurement of medical countermeasures (MCMs) against highly pathogenic viruses that can prevent morbidity and mortality from infections caused by these agents. To date, antiviral drug development has been largely focused on clinically prevalent chronic infections due to their commercial viability. This has left a huge gap in the drug development path for acute infections of biodefense importance. In this review, we discuss the antiviral research and development initiatives focusing specifically on poxviruses, filoviruses, and equine encephalitis viruses (EEV). We discuss the benefits and technical challenges in the current development strategies and the hurdles in the licensure path for MCMs against these highly pathogenic viruses under the FDA Animal Rule, and we provide recommendations for the path forward.