Targeting cellular death pathways including apoptosis is a promising strategy for cancer drug discovery To date at least three major types of cell death have been distinguished, including: apoptosis, autophagy, and necrosis Increasing evidence has begun to support a role of Bcl-2-family members in the cellular pathways involved in each of these processes The induction of apoptosis in different types of tissue and in response to various stressors is a complex process that is controlled by different BCL-2 family members Pharmacologic modulation of BCL-2 proteins and apoptosis can be achieved through different ways including the use of: (1) Modified peptides; (2) Small molecule inhibitors of anti-apoptotic proteins; (3) Antisense strategies; and (4) TRAIL targeting Non-peptide based small-molecule inhibitors of signaling pathways are at present the strategy of choice given their low antigenicity and generally more favorable pharmacokinetic and pharmacodynamic features, especially as they pertain to volume of distribution and intracellular accumulation Bcl2-family inhibitors are showing impressive preclinical efficacy in animal models and are moving rapidly towards phase I and II clinical trials Appropriate preclinical studies will need to identify the optimal strategies for combining these agents, with an emphasis on the importance of dose and schedule dependency

Targeting Survival Pathways in Lymphoma

The cell-cycle is a tightly orchestrated process where sequential steps guarantee cellular growth linked to a correct DNA replication. The entire cell division is controlled by cyclin-dependent kinases (CDKs). CDK activation is balanced by the activating cyclins and CDK inhibitors whose correct expression, accumulation and degradation schedule the time-flow through the cell cycle phases. Dysregulation of the cell cycle regulatory proteins causes the loss of a controlled cell division and is inevitably linked to neoplastic transformation. Due to their function as cell-cycle brakes, CDK inhibitors are considered as tumor suppressors. The CDK inhibitors p16INK4a and p15INK4b are among the most frequently altered genes in cancer, including hematopoietic malignancies. Aberrant cell cycle regulation in hematopoietic stem cells (HSCs) bears severe consequences on hematopoiesis and provokes hematological disorders with a broad array of symptoms. In this review, we focus on the importance and prevalence of deregulated CDK inhibitors in hematological malignancies.

/pdf/cyclin-dependent-kinase-inhibitors-in-malignant-3etiay4b.pdf

Cyclin-dependent kinase inhibitors in malignant hematopoiesis

Adult acute lymphoblastic leukemia (ALL) is characterized by a high relapse rate, with the majority of patients developing chemo-resistance and ultimately dying of the disease with a 5-year survival rate of 40% (Faderl et al., 2010). Significant advances, however, have been made in cases carrying the acquired genetic alteration BCR-ABL (ALL-Ph+) targeted by tyrosine-kinase inhibitors (Ottmann & Pfeifer, 2009). Therefore, several studies have recently been carried out to look for additional, therapeutically exploitable, genetic lesions. Aberrant activation of signal transduction pathways (STP) implicated in proliferation and survival mechanisms are generally involved in leukemogenesis and drug resistance (Zhao et al., 2010). Genes in the PI3K/PTEN/AKT/mTOR, RAS/RAF/MEK/ERK, and Jak/STAT pathways are frequently mutated and their expression is often altered in hematopoietic malignancies, including ALL (McCubrey et al., 2011; Steelman et al. 2008). In addition, deregulation of survival mechanisms may confer chemo-resistance to leukemic cells, particularly involving alterations of the Bcl-2 signaling cascade, which may represent one of the most important, potentially druggable, pathways for therapeutic intervention in ALL. Starting from our studies on chemo-resistance in ALL, particularly on multidrug resistance (MDR1) expression and prognostic significance, in this chapter we will illustrate the major pathways aberrantly activated in ALL PI3K/PTEN/AKT/mTOR, RAF/RAS/MEK/ERK, and the Bcl-2 family of proteins with the ultimate goal of summarizing novel targets for

/pdf/aberrant-proliferative-and-apoptotic-pathways-in-acute-2uql7iim3q.pdf

Aberrant Proliferative and Apoptotic Pathways in Acute Lymphoblastic Leukemia (ALL): Molecular Therapies to Overcome Chemo-Resistance

Targeting cellular death pathways including apoptosis is a promising strategy for cancer drug discovery To date at least three major types of cell death have been distinguished, including: apoptosis, autophagy, and necrosis Increasing evidence has begun to support a role of Bcl-2–family members in the cellular pathways involved in each of these processes The induction of apoptosis in different types of tissue and in response to various stressors is a complex process that is controlled by different BCL-2 family members Pharmacologic modulation of BCL-2 proteins and apoptosis can be achieved through different ways including the use of: (1) Modified peptides; (2) Small molecule inhibitors of anti-apoptotic proteins; (3) Antisense strategies; and (4) TRAIL targeting Non-peptide based small-molecule inhibitors of signaling pathways are at present the strategy of choice given their low antigenicity and generally more favorable pharmacokinetic and pharmacodynamic features, especially as they pertain to volume of distribution and intracellular accumulation Bcl2-family inhibitors are showing impressive preclinical efficacy in animal models and are moving rapidly towards phase I and II clinical trials Appropriate preclinical studies will need to identify the optimal strategies for combining these agents, with an emphasis on the importance of dose and schedule dependency

Targeting Survival Pathways

Acute lymphoblastic leukaemia (ALL) is the most common leukaemia in children and third most common in adults. Although the majority of children and adults with ALL achieve a complete remission with intensive chemotherapy, relapse will occur in 20% and 50% respectively. As further intensification risks greater toxicity and may not diminish the risk of relapse, new targeted therapies with less overall toxicity are urgently needed. There have been a number of new agents recently developed directed at specific cellular pathways involved in leukaemia genesis and are beginning to make their way into early phase clinical trials. This review will highlight a number of these novel chemotherapy agents and the pathways they target in relapse ALL.

Recent Pharmacological Advances in the Treatment of Acute Lymphoblastic Leukaemia

Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Simultaneous Inhibition of the Raf/MEK/ERK and BCL-2 Pathways

Protein Expression of p15 and p21 Plays an Unfavorable Prognostic Role in Adult Acute Lymphoblastic Leukemia (ALL) Patients Independently of Their Gene Promoter Methylation Status.

The BCL-2 Antagonist ABT-737 Is Highly Effective on Primary Acute Lymphoblastic Leukemia Cells.

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Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Simultaneous Inhibition of the Raf/MEK/ERK and BCL-2 Pathways

Protein Expression of p15 and p21 Plays an Unfavorable Prognostic Role in Adult Acute Lymphoblastic Leukemia (ALL) Patients Independently of Their Gene Promoter Methylation Status.

The BCL-2 Antagonist ABT-737 Is Highly Effective on Primary Acute Lymphoblastic Leukemia Cells.