Bryostatin 1, a unique biologic response modifier: anti-leukemic activity in vitro

Abstract

Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, has demonstrated both antineoplastic activity against the murine P388 leukemia line in vivo and stimulatory activity against mouse and human hematopoietic progenitors. We studied the effects of bryostatin 1 on the growth of human leukemias in vitro. Bryostatin 1 inhibited 1 to 4 logs of clonogenic leukemia cell growth from three of four leukemia cell lines. Bryostatin 1 also inhibited, by at least 1 log, the proliferation of clonogenic acute nonlymphocytic leukemia (ANLL) cells from 10 to 12 patients with newly diagnosed or relapsed ANLL. Maximal inhibition of leukemic growth occurred at 10(-9) to 10(- 7) mol/L bryostatin 1. Interestingly, bryostatin 1 also inhibited the growth of hematopoietic progenitors from eight patients with myelodysplastic syndromes (MDS). Leukemia cells exposed to bryostatin 1 for up to 96 hours and then washed, demonstrated no substantial inhibition of clonogenic growth, indicating that the anti-leukemic effect of bryostatin 1 is cytostatic. The phorbol ester 12–0- tetradecanoylphorbol-13-acetate (TPA) produced more potent inhibition of clonogenic leukemia growth, and this inhibition was blocked by bryostatin 1. Thus, the anti-leukemic activity of bryostatin 1 may be mediated through activation of protein kinase C. Bryostatin 1 inhibits clonogenic leukemia cells at concentrations that stimulate normal hematopoietic progenitors. The differential effects of bryostatin 1 on normal and abnormal hematopoiesis suggest that bryostatin 1 may have value in the treatment of leukemias and MDS.

Anticancer Agents from Diverse Natural Sources

“…Plitidepsin (29), isolated from mediterranean tunicate Aplidium albicans is a cyclic depsipeptide and a closely related analogue of didemnum has successfully reached phase II clinical trials for solid and hematological malignant neoplasias like T cell lymphoma and myelofibrosis [203][204][205][206], and randomized phase III trial are also ongoing in patients with relapsed/refractory multiple myeloma [207][208]. It is PharmaMar's second most advanced compound and FDA has accepted the proposal made by PharmaMar for the commercial production of the drug.…”

Requirement for myeloid growth factors in the differentiation of acute promyelocytic leukaemia

“…ATO is clinically effective in the treatment of APL relapsing after therapy with ATRA and has multiple effects on APL cells including inhibiting cellular growth, inducing apoptosis, and promoting differentiation (Shao et al , 1998; Soignet et al , 1998; Cai et al , 2000; Miller et al , 2002). Bryostatin‐1 is a macrocyclic lactone that acts as a partial agonist of protein kinase C (Berkow & Kraft, 1985; Gschwendt et al , 1988) and has potent antiproliferative (Jones et al , 1990; Grant et al , 1991), cell cycle inhibitory (Matsui et al , 2002; Clark et al , 2004), and differentiating (Stone et al , 1988; Drexler et al , 1989; Matsui et al , 2002) effects on acute myeloid leukaemia cells, including APL (Song & Norman, 1999). Treatment of NB4 (Fig 5A) and clinical APL cells (Fig 6) with ATO or bryostatin‐1 induced phenotypic differentiation as measured by myeloid surface antigen expression, although the differentiation of clinical APL samples with ATO was associated with increased levels of the granulocytic cell surface antigen CD15 rather than CD11b as others have reported (Shao et al , 1998).…”

Degradation rates of phorbol esters in Jatropha curcas L. oil and pressed seeds under different storage conditions

“…Jatropha factors C1, C2, C3, C4, C5, and C6 are the PE structures identified in Jatropha seeds . Although PEs are toxic, they are considered to be effective bioactive compounds for agricultural and pharmaceutical applications . The extracted PEs from Jatropha oil are toxic to intermediate snail hosts and larvae of schistosomes as well as to the third instar larvae of Spodoptera frugiperda .…”

“…The extracted PEs from Jatropha oil are toxic to intermediate snail hosts and larvae of schistosomes as well as to the third instar larvae of Spodoptera frugiperda . Moreover, PEs also have potential for use in the treatment of diseases connected with lymphocytes and leukaemia, and PEs can be found in synthesised prostratin, which is known as an antivirus agent . Thus, the extraction and recovery of PEs will benefit any overall process related to Jatropha seed utilisation.…”