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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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| Destruction of mitochondrial transmembrane potential, which is widely regarded as one of the earliest events in the process of cell apoptosis. Mitochondria are organelles within eukaryotic cells that produce adenosine triphosphate (ATP), the main energy molecule used by the cell. For this reason, the mitochondrion is sometimes referred to as “the powerhouse of the cell”. Mitochondria produce ATP through process of cellular respiration—specifically, aerobic respiration, which requires oxygen. The citric acid cycle, or Krebs cycle, takes place in the mitochondria. The mitochondrial membrane potential is widely used in assessing mitochondrial function as it relates to the mitochondrial capacity of ATP generation by oxidative phosphorylation. The mitochondrial membrane potential is a reliable indicator of mitochondrial health. In cancer cells, ΔΨm is often decreased, which can lead to changes in cellular metabolism, increased glycolysis, increased reactive oxygen species (ROS) production, and altered cell death pathways. The membrane of malignant mitochondria is hyperpolarized (−220 mV) in comparison to their healthy counterparts (−160 mV), which facilitates the penetration of positively charged molecules to the cancer cells mitochondria. The MMP is a critical indicator of mitochondrial function, directly reflecting the organelle's capacity to generate ATP through oxidative phosphorylation. |
| 7969- | BUL, | Bullatacin triggered ABCB1-overexpressing cell apoptosis via the mitochondrial-dependent pathway |
| - | NA, | Cerv, | KBv200 |
| 7977- | BUL, | Mitochondria-mediated apoptosis induced by acetogenins from Porcelia macrocarpa (Annonaceae) in K562 chronic myeloid leukemia cells |
| - | in-vitro, | AML, | K562 |
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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