Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro

McGown, Alan T.; Jayson, Gordon C; Pettit, George R.; Haran, Muriel; Ward, Timothy H; Crowther, Derek

doi:10.1038/bjc.1998.36

Cited by 19 publications

(7 citation statements)

References 16 publications

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“…A previous study has shown a large increase in PKC activity was observed after sequential treatment with non-toxic levels of bryostatin (a PKC activator) followed by TAM. 42 Consistent with this result, our previous study revealed that PB is a PKC activator. 43 It is likely that treatment with PB followed by TAM results in difference in activation, inhibition and intracellular translocation of individual PKC isoforms.…”

Section: Discussionsupporting

confidence: 81%

Resistance to tamoxifen‐induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer

Chung

Sheu

Yang

et al. 2001

Intl Journal of Cancer

124

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Overexpression of Her2/neu is implicated in the development of resistance to the antiestrogen tamoxifen (TAM) that exerts its inhibitory effect through interaction with estrogen receptor (ER). Whereas Her2/neu and ER are believed to be important cell survival/death factors in human breast cancer cells, if and how they interact to confer resistance to hormone therapy is not known. This prompted us to investigate whether modulation of the effect of TAM occurs via the Her2/neu pathway and whether targeting the interaction between the Her2/neu pathway and the ER pathway is beneficial. There are 2 forms of ER that are localized to the cell membrane and to the nucleus. For the first time, we found that Her2/neu directly interacts with ER at the cell membrane. We then investigated the role of Her2/neu overexpression in the regulation of the cell membrane ER pathway in TAM-resistant breast cancer cells and the nature of this interaction in apoptotic signaling. Relief of TAM resistance was associated with Her2/neu downregulation and ER upregulation. TAM-induced apoptosis occurred immediately after dissociation of Her2/neu from cell membrane ER. These results demonstrate a novel mechanism by which Her2/neu regulates the cell membrane ER-coupled apoptosis and the possible involvement of the Her2/neu in TAM resistance of breast cancer cells. Moreover, the antiproliferative activity of TAM should rely on the integration between the signal transduction from the cell membrane ER and the gene regulation by the nuclear ER. Coordinated modulation on the cell membrane ER/Her2/neu pathway and the nuclear ER/RAR pathway may provide a new approach for treatment of ER-positive, Her2/neu overexpressing breast cancer.

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Section: Discussionsupporting

confidence: 81%

Resistance to tamoxifen‐induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer

Chung

Sheu

Yang

et al. 2001

Intl Journal of Cancer

124

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“…The combined antitumor, immunopotentiating, and hematopotentiating properties of bryostatin 1 made it a promising candidate for clinical trials, and the results from the Phase I study (which began in early 1991) have demonstrated that bryostatin 1 may be administered safely (muscle soreness was the dose-limiting toxicity) and can induce a tumor response with a wide range of tumors . More recent tests have shown that bryostatin may synergize with both tamoxifen (in vitro) and paclitaxel (in vivo), and future clinical trials will probably assess the use of these combination therapies. The U.S. National Cancer Institute has moved bryostatin into Phase II trials against non-Hodgkin's lymphoma, melanoma, and renal cancer …”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Bryostatin 2

et al. 1999

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The total synthesis of the marine macrolide bryostatin 2 is described. The synthesis plan relies on aldol and directed reduction steps in order to construct the anti-1,3-diol array present in each of the principal subunits (A, B, and C). These fragments were coupled using a Julia olefination and subsequent sulfone alkylation. A series of functionalization reactions provided a bryopyran seco acid, which was macrolactonized under Yamaguchi conditions. Installation of the two enoate moieties took advantage of asymmetric phosphonate and aldol condensation strategies. Reduction of the C20 ketone and simple protecting group operations then completed the synthesis of bryostatin 2. This flexible approach should provide access to a series of new analogues of this clinically important marine natural product.

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“…However, several phase II studies were disappointing in melanoma [ 197 ], colorectal cancer [ 198 ], and gastric carcinoma [ 199 ]. Moreover, bryostatin-1 has demonstrated significant chemosensitizing activity when combined with conventional therapeutics including arabinofuranosylcytosine [ 200 ], tamoxifen [ 201 ], fludarabine [ 202 ], taxol [ 203 ] in leukemia cells. Protection of PKC from being downregulated by the strong ligand, phorbol ester, led to the design of selective PKC-binding bryostatin analogues.…”

Section: Pkc θ As Target In Clinicmentioning

confidence: 99%

The Novel PKCθfrom Benchtop to Clinic

Hage‐Sleiman

Hamze

Reslan

et al. 2015

Journal of Immunology Research

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The protein kinases C (PKCs) are a family of serine/threonine kinases involved in regulating multiple essential cellular processes such as survival, proliferation, and differentiation. Of particular interest is the novel, calcium-independent PKCθ which plays a central role in immune responses. PKCθ shares structural similarities with other PKC family members, mainly consisting of an N-terminal regulatory domain and a C-terminal catalytic domain tethered by a hinge region. This isozyme, however, is unique in that it translocates to the immunological synapse between a T cell and an antigen-presenting cell (APC) upon T cell receptor-peptide MHC recognition. Thereafter, PKCθ interacts physically and functionally with downstream effectors to mediate T cell activation and differentiation, subsequently leading to inflammation. PKCθ-specific perturbations have been identified in several diseases, most notably autoimmune disorders, and hence the modulation of its activity presents an attractive therapeutic intervention. To that end, many inhibitors of PKCs and PKCθ have been developed and tested in preclinical and clinical studies. And although selectivity remains a challenge, results are promising for the future development of effective PKCθ inhibitors that would greatly advance the treatment of several T-cell mediated diseases.

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Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro

Cited by 19 publications

References 16 publications

Resistance to tamoxifen‐induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer

Resistance to tamoxifen‐induced apoptosis is associated with direct interaction between Her2/neu and cell membrane estrogen receptor in breast cancer

Total Synthesis of Bryostatin 2

The Novel PKCθfrom Benchtop to Clinic

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