Biomedical subjects

Anthony Letai

Publications and source records attributed to Anthony Letai.

12 recordsLinked to original sources

PubMed2007

Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737.

Antiapoptotic B cell leukemia/lymphoma 2 (BCL2) family proteins are expressed in many cancers, but the circumstances under which these proteins are necessary for tumor maintenance are poorly understood. We exploited a novel functional assay that uses BCL2 homology domain 3 (BH3) peptides to predict dependence on antiapoptotic proteins, a strategy we call BH3 profiling. BH3 profiling accurately predicts sensitivity to BCL2 antagonist ABT-737 in primary chronic lymphocytic leukemia (CLL) cells. BH3 profiling also accurately distinguishes myeloid cell leukemia sequence 1 (MCL1) from BCL2 dependence in myeloma cell lines. We show that the special sensitivity of CLL cells to BCL2 antagonism arises from the requirement that BCL2 tonically sequester proapoptotic BIM in CLL. ABT-737 displaced BIM from BCL2's BH3-binding pocket, allowing BIM to activate BAX, induce mitochondrial permeabilization, and rapidly commit the CLL cell to death. Our experiments demonstrate that BCL2 expression alone does not dictate sensitivity to ABT-737. Instead, BCL2 complexed to BIM is the critical target for ABT-737 in CLL. An important implication is that in cancer, BCL2 may not effectively buffer chemotherapy death signals if it is already sequestering proapoptotic BH3-only proteins. Indeed, activator BH3-only occupation of BCL2 may prime cancer cells for death, offering a potential explanation for the marked chemosensitivity of certain cancers that express abundant BCL2, such as CLL and follicular lymphoma.

Antineoplastic Agents↗

PubMed2006

Growth factor withdrawal and apoptosis: the middle game.

In this issue of Molecular Cell, detail molecular events that trigger apoptosis following growth factor withdrawal, linking irreversible mitochondrial permeabilization to activation of GSK-3 and subsequent phosphorylation, ubiquitinylation, and degradation of the antiapoptotic BCL-2 family member MCL-1.

Apoptosis↗

PubMed2006

Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members.

We show that the antiapoptotic proteins BCL-2, BCL-XL, MCL-1, BFL-1, and BCL-w each bear a unique pattern of interaction with a panel of peptides derived from BH3 domains of BH3-only proteins. Cellular dependence on an antiapoptotic protein for survival can be decoded based on the pattern of mitochondrial sensitivity to this peptide panel, a strategy that we call BH3 profiling. Dependence on antiapoptotic proteins correlates with sequestration of activator BH3-only proteins like BID or BIM by antiapoptotic proteins. Sensitivity to the cell-permeable BCL-2 antagonist ABT-737 is also related to priming of BCL-2 by activator BH3-only molecules. Our data allow us to distinguish a cellular state we call "primed for death," which can be determined by BH3 profiling and which correlates with dependence on antiapoptotic family members for survival.

Amino Acid Sequence↗

PubMed2006

Restoring cancer's death sentence.

In this issue of Cancer Cell, two groups present data on the function of an antagonist of BCL-2, ABT-737. Both groups find that expression of MCL-1, an antiapoptotic protein related to BCL-2, is a key determinant of resistance to ABT-737. Lowering MCL-1 levels is an effective adjunct to BCL-2 antagonism, and both groups suggest ways that this might be accomplished practically in a clinical setting. The mechanism by which ABT-737 selectively kills cancer cells is discussed below in the context of these and prior reports of ABT-737's function. Antagonism of BCL-2 is an exciting anticancer strategy that may soon become a clinical reality.

Animals↗

PubMed2005

An inhibitor of Bcl-2 family proteins induces regression of solid tumours.

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.

Animals↗

PubMed2005

A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.

Bortezomib therapy has proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM); however, prolonged treatment is associated with toxicity and development of drug resistance. Here, we show that the novel proteasome inhibitor NPI-0052 induces apoptosis in MM cells resistant to conventional and Bortezomib therapies. NPI-0052 is distinct from Bortezomib in its chemical structure, effects on proteasome activities, mechanisms of action, and toxicity profile against normal cells. Moreover, NPI-0052 is orally bioactive. In animal tumor model studies, NPI-0052 is well tolerated and prolongs survival, with significantly reduced tumor recurrence. Combining NPI-0052 and Bortezomib induces synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating NPI-0052, alone and together with Bortezomib, to improve patient outcome in MM.

Administration, Oral↗

PubMed2005

BCL-2: found bound and drugged!

The BCL-2 gene was first cloned in 1985 from the t(14;18) chromosomal translocation found in nearly all follicular lymphomas. BCL-2 is understood to have a central role in inhibiting apoptosis. Now, Oltersdorf et al. report the development of a high-affinity, mechanistically validated small-molecule antagonist of BCL-2 that kills cancer in mouse xenograft models and primary human cancer cells in vitro. The two decades spanning these two achievements provide an interesting case study of rational drug development. The investigation of antiapoptotic protein antagonists holds new promise for selectively inducing programmed cell death in cancer cells.

Animals↗

PubMed2005

Pharmacological manipulation of Bcl-2 family members to control cell death.

The commitment to programmed cell death involves complex interactions among pro- and antiapoptotic members of the Bcl-2 family of proteins. The physiological result of a decision by these proteins to undergo cell death is permeabilization of the mitochondrial outer membrane. Pharmacologic manipulation of proteins in this family appears both feasible and efficacious, whether the goal is decreased cell death, as in ischemia of the myocardium or brain, or increased cell death, as in cancer.

Animals↗

PubMed2004

Antiapoptotic BCL-2 is required for maintenance of a model leukemia.

Resistance to apoptosis, often achieved by the overexpression of antiapoptotic proteins, is common and perhaps required in the genesis of cancer. However, it remains uncertain whether apoptotic defects are essential for tumor maintenance. To test this, we generated mice expressing a conditional BCL-2 gene and constitutive c-myc that develop lymphoblastic leukemia. Eliminating BCL-2 yielded rapid loss of leukemic cells and significantly prolonged survival, formally validating BCL-2 as a rational target for cancer therapy. Loss of this single molecule resulted in cell death, despite or perhaps attributable to the presence of other oncogenic events. This suggests a generalizable model in which aberrations inherent to cancer generate tonic death signals that would otherwise kill the cell if not opposed by a requisite apoptotic defect(s).

Animals↗

PubMed2003

Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1.

Regulated apoptosis is essential for both the development and the subsequent maintenance of the immune system. Interleukins, including IL-2, IL-4, IL-7 and IL-15, heavily influence lymphocyte survival during the vulnerable stages of VDJ rearrangement and later in ensuring cellular homeostasis, but the genes specifically responsible for the development and maintenance of lymphocytes have not been identified. The antiapoptotic protein MCL-1 is an attractive candidate, as it is highly regulated, appears to enhance short-term survival and functions at an apical step in genotoxic deaths. However, Mcl-1 deficiency results in peri-implantation lethality. Here we show that mice conditional for Mcl-1 display a profound reduction in B and T lymphocytes when MCL-1 is removed. Deletion of Mcl-1 during early lymphocyte differentiation increased apoptosis and arrested the development at pro-B-cell and double-negative T-cell stages. Induced deletion of Mcl-1 in peripheral B- and T-cell populations resulted in their rapid loss. Moreover, IL-7 both induced and required MCL-1 to mediate lymphocyte survival. Thus, MCL-1, which selectively inhibits the proapoptotic protein BIM, is essential both early in lymphoid development and later on in the maintenance of mature lymphocytes.

Alleles↗

PubMed2003

BH3 domains as BCL-2 inhibitors: prototype cancer therapeutics.

It is likely that most, if not all, cancer cells possess a mechanism for opposing programmed cell death, or apoptosis. One mechanism often used by cancer cells to escape apoptosis is the overexpression of B cell leukaemia/lymphoma-2 protein (BCL-2) or related antiapoptotic proteins. Inhibiting BCL-2, therefore, is an anticancer strategy worthy of attention. BCL-2 homology 3 (BH3) domains are alpha-helical segments found in BCL-2 family member proteins. In pro-apoptotic members, the BH3 domain is necessary for pro-apoptotic function. It has been shown that short peptides derived from the BH3 region possess intrinsic pro-death activity. Furthermore, certain peptides of this group exert their pro-death function by specifically binding BCL-2 and opposing BCL-2's antideath function. Therefore, BH3 domains are prototype BCL-2 inhibitors. Mimetics of BH3 domains, whether derived from peptides or small molecules, have promise as cancer therapeutics.

Animals↗

PubMed2002

Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.

The "BH3-only" proteins of the BCL-2 family require "multidomain" proapoptotic members BAX and BAK to release cytochrome c from mitochondria and kill cells. We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. Another subset characterized by the BH3 peptides from BAD and BIK cannot directly activate BAX, BAK but instead binds antiapoptotic BCL-2, resulting in the displacement of BID-like BH3 domains that initiate mitochondrial dysfunction. Transduced BAD-like and BID-like BH3 peptides also displayed synergy in killing leukemic cells. These data support a two-class model for BH3 domains: BID-like domains that "activate" BAX, BAK and BAD-like domains that "sensitize" by occupying the pocket of antiapoptotic members.

Animals↗