Phorbol ester‐induced hairy cell features on chronic lymphocytic leukemia cells in vitro

Al‐Katib, Ayad; Wang, Chang Yi; McKenzie, Susan; Clarkson, Bayard D.; Koziner, Benjamín

doi:10.1002/ajh.2830400405

Cited by 24 publications

(20 citation statements)

References 28 publications

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“…Phorbol esters have been reported to induce differentiation of CLL cells. 37 Bryostatin 1 is a structurally related compound lacking the tumor-promoting effects of phorbol esters. Bryostatin 1 induces morphological changes in CLL, including an increase in cell size, irregularity in cell shape, and formation of cytoplasmatic extensions ( Figure 1A).…”

Section: Discussionmentioning

confidence: 99%

The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion

Biberacher¹,

Decker²,

Oelsner³

et al. 2011

Haematologica

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BackgroundIn spite of potent first-line therapies for chronic lymphocytic leukemia, treatment remains palliative and all patients frequently relapse. Treatment options for these patients are more limited. BL22 is a recombinant protein composed of the variable region of a monoclonal antibody that binds to CD22 and of PE38, a truncated Pseudomonas exotoxin. BL22 is a very potent drug already used in patients with hairy cell leukemia, whereas in chronic lymphocytic leukemia its cytotoxicity is limited by a lower expression of CD22. Here we demonstrate that this limitation can be overcome by pre-activation of chronic lymphocytic leukemia cells with bryostatin 1. Design and MethodsPrimary malignant B cells from chronic lymphocytic leukemia and mantle cell lymphoma patients were used in vitro to assess the therapeutic impact of drug combinations using BL22 and bryostatin 1. ResultsWe demonstrate that bryostatin 1 sensitizes chronic lymphocytic leukemia cells for the cytotoxic effects of BL22 through activation of protein kinase C and subsequently increased CD22 surface expression. Dose and time response analysis reveals that activation of protein kinase C further activates an autocrine feedback loop degrading protein kinase C-βII protein. Depletion of protein kinase C-βII and upregulation of CD22 persist for several days following pre-stimulation with bryostatin 1. Therefore, our data provide a rationale for the sequential administration of BL22 following bryostatin 1 treatment. In addition to primary chronic lymphocytic leukemia cells, bryostatin 1 also sensitizes diffuse large B-cell lymphoma and mantle cell lymphoma cells to BL22 induced apoptosis. ConclusionsOur data suggest that the combination of bryostatin 1 with antibodies directed against CD22 is a potent drug combination for the treatment of low-and high-grade B-cell lymphoma.Key words: CLL, bryostatin 1, CD22, immunotoxin, B-cell lymphoma. CD22 upregulation and PKC-βII depletion. Haematologica 2012;97(5):771-779. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Biberacher V, Decker T, Oelsner M, Wagner M, Bogner C, Schmidt B, Kreitman RJ, Peschel C, Pastan I, Meyer zum Büschenfelde C and Ringshausen I. The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC-βII depletion

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Section: Discussionmentioning

confidence: 99%

The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion

Biberacher¹,

Decker²,

Oelsner³

et al. 2011

Haematologica

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“…Bryostatin also appears to enhance fludarabine induction of apoptosis of leukemia cells [19]. Treatment of CLL cells in vitro with bryostatin alters the morphology and the phenotype to resemble hairy cells [22]. A series of studies are evaluating combinations of bryostatin with purine analogues.…”

Section: Bryostatinmentioning

confidence: 98%

New drug development in non-hodgkin lymphomas

Cheson

2001

Curr Oncol Rep

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The non-Hodgkin lymphomas (NHL) are characterized by initial responsiveness to a variety of chemotherapeutic regimens. Nevertheless, most patients progress and die from their disease. A number of new agents with unique mechanisms of action are in clinical development. Agents that are currently considered to be the most promising include those that induce apoptosis; those that interfere with cell cycling, tumor-associated angiogenesis, farnesylation of the Ras gene, and histone deacetylase; and those that inhibit the proteasome, among others. Increasing insights into the differences between tumors and among patients will lead to more individualized therapeutic strategies using agents directed at specific genetic and immunologic targets. More rapid accrual to high-quality clinical studies will facilitate dissemination of new agents to patients and lead to an increased cure rate for NHL.

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“…348 This drug has been shown to induce terminal differentiation of B-cell morphology and a phenotype resembling hairy cell leukemia. 349,350 Preclinical studies have suggested a synergistic action between bryostatin and purine analogues or interferon alfa. [351][352][353] Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, causes cell cycle inhibition at G 1 and G 2 M 354,355 and rapidly induces apoptosis in a cell cycle-and p53-independent manner.…”

Section: New Drugsmentioning

confidence: 99%

B‐chronic lymphocytic leukemia: practical aspects

Pangalis

Vassilakopoulos

Dimopoulou

et al. 2002

Hematological Oncology

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B-CLL is the most common adult leukemia in the Western world. It is a neoplasia of mature looking B-monoclonal lymphocytes co-expressing the CD5 antigen (involving the blood, the bone marrow, the lymph nodes and related organs). Much new information about the nature of the neoplastic cells, including chromosomal and molecular changes as well as mechanisms participating in the survival of the leukemic clone have been published recently, in an attempt to elucidate the biology of the disease and identify prognostic subgroups. For the time being, clinical stage based on Rai and Binet staging systems remains the strongest predictor of prognosis and patients' survival, and therefore it affects treatment decisions. In the early stages treatment may be delayed until progression. When treatment is necessary according to well-established criteria, there are nowadays many different options. Chlorambucil has been the standard regimen for many years. During the last decade novel modalities have been tried with the emphasis on fludarabine and 2-chlorodeoxyadenosine and their combinations with other drugs. Such an approach offers greater probability of a durable complete remission but no effect on overall survival has been clearly proven so far. Other modalities, included in the therapeutic armamentarium, are monoclonal antibodies, stem cell transplantation (autologous or allogeneic) and new experimental drugs. Supportive care is an important part of patient management and it involves restoring hypogammaglobulinemia and disease-related anemia by polyvalent immunoglobulin administration and erythropoietin respectively.

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Phorbol ester‐induced hairy cell features on chronic lymphocytic leukemia cells in vitro

Cited by 24 publications

References 28 publications

The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion

The cytotoxicity of anti-CD22 immunotoxin is enhanced by bryostatin 1 in B-cell lymphomas through CD22 upregulation and PKC- II depletion

New drug development in non-hodgkin lymphomas

B‐chronic lymphocytic leukemia: practical aspects

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