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| Bullatacin - Annonaceous Acetogenin Type: Annonaceous acetogenin / bioactive natural compound Sources: Bullatacin occurs in plants of the Annonaceae family and has been isolated from Annona atemoya. Function: Bullatacin is a highly cytotoxic annonaceous acetogenin that interferes with cellular energy metabolism and mitochondrial electron transport. It has also been reported to inhibit NADH oxidase activity and alter intracellular signaling associated with tumor-cell survival. Cancer: Preclinical studies demonstrate potent antiproliferative and pro-apoptotic activity. Bullatacin inhibits hepatoma-cell proliferation, induces apoptosis, and has shown antitumor activity in experimental tumor models. Reported mechanisms include inhibition of mitochondrial energy metabolism, NADH oxidase activity, and reductions in intracellular cAMP and cGMP signaling. Clinical anticancer efficacy has not been established. Bullatacin — a highly lipophilic Annonaceous acetogenin and potent mitochondrial poison isolated from plants of the Annonaceae family, including Annona atemoya and Annona bullata. It is formally classified as a natural-product acetogenin and experimental cytotoxic/antitumor agent. Bullatacin is best characterized as a mitochondrial complex I inhibitor that suppresses oxidative phosphorylation and cellular ATP production. It has unusually high cytotoxic potency in several cancer-cell models, including multidrug-resistant cells, but has no established therapeutic use in humans. Its mechanism overlaps substantially with that of other neurotoxic Annonaceous acetogenins. Primary mechanisms (ranked):
Bioavailability / PK relevance: Human pharmacokinetics have not been established. Bullatacin is highly lipophilic, but there is insufficient validated systemic PK information to define clinically achievable plasma or tumor concentrations. Effective experimental concentrations can be in the low-nanomolar range, and antitumor activity has been demonstrated in some mouse models after parenteral dosing. However, efficacy and toxicity appear to have a narrow and model-dependent relationship. There is no established oral dose, therapeutic window, formulation, or human exposure target. In-vitro vs systemic exposure relevance: Bullatacin frequently produces cellular effects at nanomolar concentrations, including approximately 10 nM in colon-cancer immunogenic-cell-death studies and an approximately 7.8 nM one-day ED50 in hepatoma cells. These concentrations cannot presently be compared reliably with achievable human systemic exposure because human PK data are lacking. The mitochondrial complex-I mechanism is concentration-driven and is not cancer-specific; systemic exposure therefore raises substantial normal-tissue and neurological safety concerns. Clinical evidence status: Preclinical only. Evidence consists predominantly of biochemical studies, cancer-cell experiments, and animal tumor models. Some murine models have demonstrated tumor-growth inhibition, while at least one ovarian tumor model found no survival benefit within nonlethal dosing ranges. No established human anticancer trials, approved indication, or regulatory therapeutic use for bullatacin was identified. The Annonaceous acetogenin class has an important neurotoxicity signal, including experimental mitochondrial complex-I-mediated neurodegeneration and epidemiologic associations between chronic Annonaceae exposure and atypical parkinsonism. Bullatacin Mechanistic Profile
P: 0–30 min R: 30 min–3 hr G: >3 hr |
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| Cytochrome c ** The term "release of cytochrome c" ** an increase in level for the cytosol. Small hemeprotein found loosely associated with the inner membrane of the mitochondrion where it plays a critical role in cellular respiration. Cytochrome c is highly water-soluble, unlike other cytochromes. It is capable of undergoing oxidation and reduction as its iron atom converts between the ferrous and ferric forms, but does not bind oxygen. It also plays a major role in cell apoptosis. The term "release of cytochrome c" refers to a critical step in the process of programmed cell death, also known as apoptosis. In its new location—the cytosol—cytochrome c participates in the apoptotic signaling pathway by helping to form the apoptosome, which activates caspases that execute cell death. Cytochrome c is a small protein normally located in the mitochondrial intermembrane space. Its primary role in healthy cells is to participate in the electron transport chain, a process that helps produce energy (ATP) through oxidative phosphorylation. Mitochondrial outer membrane permeability leads to the release of cytochrome c from the mitochondria into the cytosol. The release of cytochrome c is a pivotal event in apoptosis where cytochrome c moves from the mitochondria to the cytosol, initiating a chain reaction that leads to programmed cell death. On the one hand, cytochrome c can promote cancer cell survival and proliferation by regulating the activity of various signaling pathways, such as the PI3K/AKT pathway. This can lead to increased cell growth and resistance to apoptosis, which are hallmarks of cancer. On the other hand, cytochrome c can also induce apoptosis in cancer cells by interacting with other proteins, such as Apaf-1 and caspase-9. This can lead to the activation of the intrinsic apoptotic pathway, which can result in the death of cancer cells. Overexpressed in Breast, Lung, Colon, and Prostrate. Underexpressed in Ovarian, and Pancreatic. |
| 7969- | BUL, | Bullatacin triggered ABCB1-overexpressing cell apoptosis via the mitochondrial-dependent pathway |
| - | NA, | Cerv, | KBv200 |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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