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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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| In all eukaryotic cells, intracellular Ca2+ levels are maintained at low resting concentrations (approximately 100 nM) by the activity of the major Ca2+ extrusion system, the plasma membrane Ca2+-ATPase (PMCA), which exchanges extracellular protons (H+) for cytosolic Ca2+. Indeed, sustained elevation of [Ca2+]C in the form of overload, saturating all Ca2+-dependent effectors, prolonged decrease in [Ca2+]ER, causing ER stress response, and high [Ca2+]M, inducing mitochondrial permeability transition (MPT), are considered to be pro-death factors. In cancer the Ca2+-handling toolkit undergoes profound remodelling (figure 1) to favour activation of Ca2+-dependent transcription factors, such as the nuclear factor of activated T cells (NFAT), c-Myc, c-Jun, c-Fos that promote hypertrophic growth via induction of the expression of the G1 and G1/S phase transition cyclins (D and E) and associated cyclin-dependent kinases (CDK4 and CDK2). Thus, cancer cells may evade apoptosis through decreasing calcium influx into the cytoplasm. This can be achieved by either downregulation of the expression of plasma membrane Ca2+-permeable ion channels or by reducing the effectiveness of the signalling pathways that activate these channels. Such protective measures would largely diminish the possibility of Ca2+ overload in response to pro-apoptotic stimuli, thereby impairing the effectiveness of mitochondrial and cytoplasmic apoptotic pathways. Voltage-Gated Calcium Channels (VGCCs): Overexpression of VGCCs has been associated with increased tumor growth and metastasis in various cancers, including breast and prostate cancer. Store-Operated Calcium Entry (SOCE): SOCE mechanisms, such as STIM1 and ORAI1, are often upregulated in cancer cells, contributing to enhanced cell survival and proliferation. High intracellular calcium levels are associated with increased cell proliferation and migration, leading to a poorer prognosis. Calcium signaling can also influence hormone receptor status, affecting treatment responses. Increased Ca²⁺ signaling is associated with advanced disease and metastasis. Patients with higher CaSR expression may have a worse prognosis due to enhanced tumor growth and resistance to apoptosis. -Ca2+ is an important regulator of the electric charge distribution of bio-membranes. |
| 7976- | BUL, | Antitumor activity and toxicity relationship of annonaceous acetogenins |
| - | in-vitro, | HCC, | H22 |
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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