Targeting the Apo2L/TRAIL system for the therapy of autoimmune diseases and cancer

Apo 2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL), is a member of the TNF family of cytokines, which can induce apoptotic cell death in cells expressing at least one of their specific death receptors, DR4 (TRAIL-R1) or DR5 (TRAIL-R2). In the last decade, the Apo2L/TRAIL system of apoptosis has attracted significant interest as a potential drug-targeting pathway for human therapy, due to the ability of that cytokine to trigger apoptosis in various types of cancer cells while displaying low or no toxicity to normal cells. Recent results suggest that manipulating the Apo2L/TRAIL system may be also useful for the treatment of inflammatory disorders such as rheumatoid arthritis. For its possible therapeutic use, a number of receptor-specific Apo2L/TRAIL molecular variants and agonistic monoclonal antibodies have been developed, and some of them are in clinical trials. In addition, Apo2L/TRAIL-resistant tumors can be sensitized to Apo2L/TRAIL by selected novel or classical chemotherapeutic agents, opening new possibilities for combined therapies. We will briefly review the current status of Apo2L/TRAIL-based therapies for human disease, their promises and limitations.     

Targeting TRAIL in the treatment of cancer: new developments

Introduction: While apoptosis is critical for maintaining homeostasis in normal cells, defective apoptosis contributes to the survival of cancer cells. TNF-related apoptosis-inducing ligand (TRAIL)-targeted therapy has attracted significant effort for treating cancer, but the clinical results have revealed limitations. The authors review the current status of development of TRAIL-targeted therapy with an outlook towards the future.

Areas covered: Recombinant human proteins, small molecules and agonistic monoclonal antibodies targeting death receptors that trigger TRAIL-mediated apoptosis are covered in this article. The authors review both intrinsic and extrinsic apoptotic pathways, highlighting how the apoptosis serves as a promising therapeutic target. They also review different categories of TRAIL pathway targeting agents and provide a brief overview of clinical trials using these agents. The authors discuss the limitations of conventional approaches for targeting the TRAIL pathway as well as future directions.

Expert opinion: The development of better combination partners for pro-apoptotic TRAIL pathway modulators including novel agents inhibiting anti-apoptotic molecules or targeting alternative resistance pathways may improve the chances for anti-tumor responses in the clinic. Developing predictive biomarkers via circulating tumor cells/DNA, apoptosis signal products, and genetic signatures/protein biomarkers from tumor tissue are also suggested as future directions.     

Targeting death receptors in cancer with Apo2L/TRAIL

Unlike conventional cancer therapeutics, death receptor ligands trigger tumor cell apoptosis independently of the p53 tumor suppressor gene, which frequently is inactivated in cancer. The death receptor ligand Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) offers promising therapeutic potential based on its ability to induce apoptosis in various cancer cell lines with little toxicity toward normal cells. Moreover, Apo2L/TRAIL displays single-agent activity and cooperates with chemotherapy or radiotherapy in a variety of tumor xenograft mouse models. Thus, Apo2L/TRAIL might be effective against tumors that have acquired resistance to conventional therapy, and could augment the efficacy of current treatment in a wide spectrum of cancers.     

Sulfatides for the treatment of autoimmune disorders

Natural killer T (NKT) cells are a subset of immune regulatory cells. Several glycolipids and phospholipids derived from mammalian, bacterial, protozoan and plant species have recently been identified as possible natural ligands for NKT cells. One such compound, sulfatide, which is a major glycolipid of myelin, has been shown to modulate NKT cell activity. This patent application claims to ameliorate or prevent symptoms of immune related disorders by application of sulfatides. Although preclinical studies have effectively targeted NKT cells for immunotherapy, little is known regarding the early in vivo response of these cells to antigenic stimulation. The data in support of the present patent may suggest that the naturally β-anomeric glycosphingolipids (sulfatides) may be ligands for NKT lymphocytes.     

Cooperation between Apo2L/TRAIL and bortezomib in multiple myeloma apoptosis

The proteasome inhibitor bortezomib is currently an important drug for treatment of relapsed and refractory multiple myeloma (MM) and for elderly patients. However, cells from some patients show resistance to bortezomib. We have evaluated the possibility of improving bortezomib therapy with Apo2L/TRAIL, a death ligand that induces apoptosis in MM but not in normal cells. Results indicate that cotreatment with low doses of bortezomib significantly increased apoptosis of MM cells showing partial sensitivity to Apo2L/TRAIL. Bortezomib treatment did not significantly alter plasma membrane amount of DR4 and DR5 but increased Apo2L/TRAIL-induced caspase-8 and caspase-3 activation. Apo2L/TRAIL reverted bortezomib-induced up-regulation of β-catenin, Mcl-1 and FLIP, associated with the enhanced cytotoxicity of combined treatment. More important, some cell lines displaying resistance to bortezomib were sensitive to Apo2L/TRAIL-induced apoptosis. A cell line made resistant by continuous culture of RPMI 8226 cells in the presence of bortezomib (8226/7B) was highly sensitive to Apo2L/TRAIL-induced apoptosis. Moreover, RPMI 8226 cells overexpressing Mcl-1 (8226/Mcl-1) or Bcl-x_L (8226/Bcl-x_L) also showed enhanced resistance to bortezomib, but co-treatment with Apo2L/TRAIL reverted this resistance. These results indicate that Apo2L/TRAIL can cooperate with bortezomib to induce apoptosis in myeloma cells and can be an useful adjunct for MM therapy.     

Concepts in the use of TRAIL/Apo2L: an emerging biotherapy for myeloma and other neoplasias

TNF-related apoptosis inducing ligand/Apo2 ligand (TRAIL/Apo2L) is a member of the TNF superfamily of death ligands that selectively induces apoptosis in tumour cells of diverse origins. In this report, we have reviewed recent studies examining TRAIL/Apo2L-induced apoptosis in multiple myeloma (MM), a B-cell malignancy which, in spite of its initial sensitivity to steroids, cytotoxic and high-dose chemotherapy, remains incurable. Recently, we demonstrated that TRAIL/Apo2L induces apoptosis of steroid- and chemotherapy-sensitive and resistant MM cell lines. Moreover, TRAIL/Apo2L selectively induced apoptosis of patient MM tumour cells while sparing non-malignant bone marrow and peripheral blood mononuclear cells. In addition, TRAIL/Apo2L inhibited the growth of human plasmacytomas xenografted into mice. Importantly, TRAIL/Apo2L-induced apoptosis was unaffected by IL-6, a potent growth and survival factor for MM cells which, as we and others have previously shown, blocks various pro-apoptotic signals including Fas ligand, which like TRAIL/Apo2L is also a member of the TNF family of ligands. In view of the potential clinical application of TRAIL/Apo2L to the treatment of MM, we have attempted to discern intracellular mechanisms of action and resistance for TRAIL/Apo2L in MM, along with strategies to increase sensitivity and overcome resistance of MM cells to TRAIL/Apo2L. These studies demonstrated that doxorubicin, an agent which is commonly used to treat MM patients, upregulated the expression of the DR5 death-signalling TRAIL receptor and synergistically enhanced the pro-apoptotic effect of TRAIL on MM cells. Moreover, NF-κB inhibitors such as SN50 (a cell permeable inhibitor of NF-κB nuclear translocation) as well as the proteasome inhibitor PS-341, which is currently in Phase II clinical trials, also enhanced the pro-apoptotic activity of TRAIL/Apo2L in MM cells. Lastly, TRAIL/Apo2L-induced apoptosis in MM cells was dependent on caspase-8 activation and inhibited by the caspase regulatory proteins FLIP and cIAP2. These studies provide a framework for the use of TRAIL/Apo2L as a single agent or as part of combination therapy for the treatment of MM.     

Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship

Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).     

斑秃治疗的疗效观察以及免疫功能紊乱的研究

目的：观察卡介菌多糖核酸注射液（迪苏）联合5％米诺地尔酊（蔓迪）治疗斑秃疗效进行斑秃免疫功能紊乱的研究。方法：60例斑秃患者分为两组,分别采用卡介菌多糖核酸注射液联合5％米诺地尔酊治疗（联合治疗组）、单用卡介菌多糖核酸治疗（对照组）。同时对60例患者进行自身血清皮肤试验。结果：两组临床治疗效果差异有统计学意义,X2=4.1761,P=0.041;自身血清皮肤试验的阳性率为68.33%。结论：本研究提示自身免疫功能紊乱参与斑秃的发病,联合多途径治疗斑秃的方法在临床上值得推广。     

Management of autoimmune skin disorders in the elderly

Senescence of the skin immunological system may explain why the elderly population has an increased susceptibility to certain autoimmune skin disorders. These disorders are characterised by the production of either antibodies that react with host tissue or immune effector T cells that are autoreactive. Bullous pemphigoid is the most common autoimmune blistering disease in the elderly. Although oral corticosteroids are the best established therapy, high-potency topical corticosteroids are very useful as initial treatment and, in the elderly, should be used instead of oral prednisolone wherever possible. Pemphigus is a chronic blistering disease of which there are two main subtypes: vulgaris and foliaceous. Paraneoplastic pemphigus is a unique clinical, histological and immunologically distinct autoimmune mucocutaneous disease which tends to be relentlessly progressive. Lichen sclerosus presents specific complications and a small but definite increased risk of squamous cell carcinoma in elderly patients. It is important to be aware of practical issues such as the difficulty in applying topical corticosteroids, the mainstay treatment of this condition. Dermatomyositis is an autoimmune systemic disorder where the skin and muscles are the most commonly affected organs. Tumour-associated disease occurs more commonly in elderly patients and has a poorer prognosis. Management of the disease includes sunscreens, topical or systemic corticosteroids, antimalarials, oral immunosuppressants or intravenous immunoglobulins. It is important to bear in mind that old age modifies the management of skin diseases because of physical and social circumstances as well as the unwanted adverse effects of medications. Polypharmacy results in an increased risk of drug interactions and, therefore, drug regimens need to be kept as simple as possible. Drug-induced autoimmune skin eruptions are common amongst the elderly and usually resolve when the offending drug is discontinued.     

B cell depletion in autoimmune diabetes: insights from murine models

Introduction: The incidence of type 1 diabetes (T1D) is rising for reasons that largely elude us. New strategies aimed at halting the disease process are needed. One type of immune cell thought to contribute to T1D is the B lymphocyte. The first Phase II trial of B cell depletion in new onset T1D patients indicated that this slowed the destruction of insulin-producing pancreatic beta cells. The mechanistic basis of the beneficial effects remains unclear.

Areas covered: Studies of B cell depletion and deficiency in animal models of T1D. How B cells can influence T cell-dependent autoimmune diabetes in animal models. The heterogeneity of B cell populations and current evidence for the potential contribution of specific B cell subsets to diabetes, with emphasis on marginal zone B cells and B1 B cells.

Expert opinion: B cells can influence the T cell response to islet antigens and B cell depletion or genetic deficiency is associated with decreased insulitis in animal models. New evidence suggests that B1 cells may contribute to diabetes pathogenesis. A better understanding of the roles of individual B cell subsets in disease will permit fine-tuning of therapeutic strategies to modify these populations.     

B cell depletion in autoimmune diabetes: insights from murine models

INTRODUCTION: The incidence of type 1 diabetes (T1D) is rising for reasons that largely elude us. New strategies aimed at halting the disease process are needed. One type of immune cell thought to contribute to T1D is the B lymphocyte. The first Phase II trial of B cell depletion in new onset T1D patients indicated that this slowed the destruction of insulin-producing pancreatic beta cells. The mechanistic basis of the beneficial effects remains unclear. AREAS COVERED: Studies of B cell depletion and deficiency in animal models of T1D. How B cells can influence T cell-dependent autoimmune diabetes in animal models. The heterogeneity of B cell populations and current evidence for the potential contribution of specific B cell subsets to diabetes, with emphasis on marginal zone B cells and B1 B cells. EXPERT OPINION: B cells can influence the T cell response to islet antigens and B cell depletion or genetic deficiency is associated with decreased insulitis in animal models. New evidence suggests that B1 cells may contribute to diabetes pathogenesis. A better understanding of the roles of individual B cell subsets in disease will permit fine-tuning of therapeutic strategies to modify these populations.     

Tolvaptan: a new tool for the effective treatment of hyponatremia in psychotic disorders

Importance of the field: Hyponatremia (serum sodium concentration <?136 mEq/liter) is a common and potentially life-threatening medical comorbidity seen in patients with psychotic disorders. Tolvaptan, a selective antagonist of the V₂-receptor, is FDA-approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. This represents a major development in the care of psychotic individuals with hyponatremia.

Areas covered in the review: This review provides an overview of the existing literature on prevalence rates and risk factors associated with hyponatremia in psychotic patients (1923 – present). Tolvaptan is discussed as a potential advance in the treatment of hyponatremia in patients with psychotic disorders, and preliminary data are reviewed.

What the reader will gain: The reader will gain an appreciation of the prevalence of hyponatremia among psychotic individuals, an understanding of the distinctions between acute and chronic hyponatremia in this population, and awareness that effective treatments are becoming available.

Take home message: A modest literature exists regarding prevalence rates and risk factors associated with hyponatremia in psychotic populations. Hyponatremia is common and serious enough to merit clinical concern. Perhaps, now that tolvaptan has been FDA-approved, progress will accelerate and new insights will develop that begin to bring relief from this medical comorbidity among psychotic patients.     

PK/PD: new insights for antibacterial and antiviral applications

The path of new compounds from discovery to bedside is long and costly and a large majority of compounds never make it to the market. To improve drug development, better tools are needed to assess efficacy and safety early in the process. One approach that has been suggested by the FDA to help streamlining the drug development process is pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. In this approach, a model-based link between PK profiles and corresponding PD is established. Once a suitable model is identified and validated, predictions about efficacy and safety of different dosing regimens can be made. The goal of this review is to examine the current state of PK, PD, and PK/PD in antibiotic and antiviral research and development.     

Granisetron: new insights into its use for the treatment of chemotherapy-induced nausea and vomiting

Granisetron (Kytril, Roche) is a 5-hydroxytryptamine 3 (5-HT(3))-receptor antagonist indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin. Its indication expanded in August 2002, with approval from the FDA for the prevention and treatment of postoperative nausea and vomiting. Granisetron strongly and selectively binds to the 5-HT(3) receptor with a binding constant of 0.26 nM and exhibits a 4000 - 40,000 times greater binding affinity for the 5-HT(3) receptor than other binding sites, including other 5HT subtypes and adrenergic, histaminergic and opioid receptors. Its selectivity to the 5-HT(3) receptor over other receptor types is > 1000:1. Granisetron noncompetitively binds to the 5-HT(3) receptor and is associated with a long duration of action as shown by the inhibition of a 5-HT axonal response flare for up to 24 h. Granisetron is unique among the 5-HT(3)-receptor antagonists because it is not metabolised via the cytochrome P450 (CYP) 2D6 pathway and is, therefore, less susceptible to variation in patient response because of factors such as pharmacogenomic differences. Granisetron and other 5-HT(3)-receptor antagonists are first-line agents for acute chemotherapy-induced nausea and vomiting (CINV), whereas combination therapy with 5-HT(3)-receptor antagonists, dexamethasone and neurokinin (NK)-1 receptor antagonism (i.e., with the recently approved aprepitant) is an effective approach to prevent delayed CINV. Granisetron has been shown to be an effective within-class rescue antiemetic for prophylactic failures, which may be linked to its pharmacological properties including non-competitive, insurmountable binding to the 5-HT(3) receptor. As with other 5-HT(3)-receptor antagonists, granisetron is well-tolerated with adverse events of mild severity including headache, asthenia and constipation. Overall, data demonstrate that granisetron is an efficacious, safe and cost-effective member of the 5HT(3)-receptor antagonist class for the prevention of CINV.     

Granisetron: new insights into its use for the treatment of chemotherapy-induced nausea and vomiting

Granisetron (Kytril^®, Roche) is a 5-hydroxytryptamine 3 (5-HT₃)-receptor antagonist indicated for the prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin. Its indication expanded in August 2002, with approval from the FDA for the prevention and treatment of postoperative nausea and vomiting. Granisetron strongly and selectively binds to the 5-HT₃ receptor with a binding constant of 0.26 nM and exhibits a 4000 – 40,000 times greater binding affinity for the 5-HT₃ receptor than other binding sites, including other 5HT subtypes and adrenergic, histaminergic and opioid receptors. Its selectivity to the 5-HT₃ receptor over other receptor types is > 1000:1. Granisetron noncompetitively binds to the 5-HT₃ receptor and is associated with a long duration of action as shown by the inhibition of a 5-HT axonal response flare for up to 24 h. Granisetron is unique among the 5-HT₃-receptor antagonists because it is not metabolised via the cytochrome P450 (CYP) 2D6 pathway and is, therefore, less susceptible to variation in patient response because of factors such as pharmacogenomic differences. Granisetron and other 5-HT₃-receptor antagonists are first-line agents for acute chemotherapy-induced nausea and vomiting (CINV), whereas combination therapy with 5-HT₃-receptor antagonists, dexamethasone and neurokinin (NK)-1 receptor antagonism (i.e., with the recently approved aprepitant) is an effective approach to prevent delayed CINV. Granisetron has been shown to be an effective within-class rescue antiemetic for prophylactic failures, which may be linked to its pharmacological properties including non-competitive, insurmountable binding to the 5-HT₃ receptor. As with other 5-HT₃-receptor antagonists, granisetron is well-tolerated with adverse events of mild severity including headache, asthenia and constipation. Overall, data demonstrate that granisetron is an efficacious, safe and cost-effective member of the 5HT₃-receptor antagonist class for the prevention of CINV.     

Involvement of membrane channels in autoimmune disorders

Ion channels are ubiquitous transmembrane proteins that are involved in a wide variety of cellular functions by selectively controlling the passage of ions across the plasma membrane. Among these functions many immune processes, including those in autoimmune reactions, also rely on the operation of ion channels, but the roles of ion channels can be very diverse. Here the participation of ion channels in three different roles in autoimmune processes is discussed: 1. ion channels in effector immune cells attacking other tissues causing autoimmune diseases, such as multiple sclerosis; 2. ion channels as direct targets of the immune system whereby loss of channel function leads to disease, as in myasthenia gravis; 3. ion channels whose function is modulated in the target cells by an apoptotic signal transduction cascade, such as the Fas/Fas ligand pathway. The numerous tasks that ion channels perform in autoimmune disorders and the wealth of information that has been gathered about them in recent years together provide a good basis for the design and production of drugs that may be effectively used in the therapy of these diseases.