Arenobufagin

Source: Wikipedia, the free encyclopedia.
Arenobufagin
Names
IUPAC name
5-[(3S,5R,10S,11S,13R,14S,17R)-3,11,14-trihydroxy-10,13-dimethyl-12-oxo-2,3,4,5,6,7,8,9,11,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]pyran-2-one
Other names
Arenobufagin
Identifiers
3D model (
JSmol
)
ChemSpider
UNII
  • InChI=1S/C24H32O6/c1-22-9-7-15(25)11-14(22)4-5-17-19(22)20(27)21(28)23(2)16(8-10-24(17,23)29)13-3-6-18(26)30-12-13/h3,6,12,14-17,19-20,25,27,29H,4-5,7-11H2,1-2H3/t14-,15+,16-,17-,19-,20+,22+,23+,24+/m1/s1 checkY
    Key: JGDCRWYOMWSTFC-AZGSIFHYSA-N checkY
  • C[C@]12CC[C@@H](C[C@H]1CCC3C2[C@@H](C(=O)[C@]4([C@@]3(CC[C@@H]4C5=COC(=O)C=C5)O)C)O)O
Properties
C24H32O6
Molar mass 416.514 g·mol−1
Appearance liquid
Density 1.4±0.1 g/cm3
Boiling point 637.2±55.0 °C at 760 mmHg
Vapor pressure 0.0±4.3 mmHg at 25 °C
1.622
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Cardiotoxic
GHS labelling:
GHS06: Toxic
Danger
Flash point 219.3±25.0 °C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Arenobufagin is a

Bufo arenarum.[1] It has effects similar to digitalis, blocking the Na+/K+ pump in heart tissue.[2]

Sources

The compound arenobufagin is one of the major components of

Bufo gargarizans and Bufo melanostictus Suhneider. Arenobufagin is specifically secreted by Rhinella arenarum, which is found in South America. The venom of these toad species contains about 1.75% of arenobufagin.[3] The other major part of the venom consists mostly of similar looking bufagins, which are all toxic steroids
. Toads produce their venom when they are scared, injured, or provoked, as a defense mechanism against their predators.

History

Arenobufagin is a component of a certain toad venom which goes by the name of Chan’su. For centuries, this venom has been used in

tumor cells. In fact, this compound showed the most potent antitumor activity of fifteen bufadionolides isolated from Chan’su.[4]

Function in medicine

As already mentioned, arenobufagin has been widely used in traditional Chinese medicine (TCM) to tackle down carcinogenesis , since it inhibits cell growth in several cancer cells. It is one of the central active ingredients of toad venom for treatment.[5] This happens both in purified form or in combination with other ingredients, which are mostly herbal components. Toad venom is in fact still used in clinical practice of in TCM to treat hepatocellular carcinoma (HCC).[6] So far there is still little known about the anti-angiogenic properties of Arenobufagin. One studie shows that Arenobufagin inhibits VEGF-induced endothial cell tube formation.[7]

Intake

Under normal circumstances, arenobufagin is a

Chinese traditional medicine, it in ingested either orally or topically, for example to the skin. Little is known about its toxicokinetics
.

Toxicodynamics

Proposed model of arenobufagin interactions

Arenobufagin is believed to play a role in the regulation of the transport of water and electrolytes across

lipophilic
that ouabain and as such form a more stable complex with the Na+-K+ pump.

Besides its effects on the Na+-K+ pump, arenobufagin also has some other effects on

cancer cell lines
. It causes
Bax/Bcl-2 ratio, which is associated with apoptosis, or programmed cell death. Bax translocation from cytosol
to mitochondria was also found to be increased. In addition to these effects, arenobufagin also induces morphological changes in
PARP
) and a decrease in pro-caspase9 and 3 were also induced by arenobufagin treatment. PARP is mainly involved in cell repair and programmed cell death. After treatment with arenobufagin, some cells make more
caspase-3
cleavage. This indicates that autophagy pathways protect the cell against apoptosis by arenobufagin. It was hypothesized that arenobufagin may inhibit the
Akt pathway in controlling cell death and differentiation in response to external stimuli. It was found that arenobufagin inhibited the proteins Akt, PDK1 and PI3K, whereas it stimulated the PHEN-protein. It does this by altering the degree of phosphorylation. All these proteins are involved in the PI3/Akt pathway. Further down the pathway, arenobufagin indirectly inhibits the mTOR-protein, which is involved in apoptosis as well as in autophagy.[8]

Detoxification

The biotransformation of arenobufagin by Alternaria alternata leads to the following three metabolites: 3-oxo-arenobufagin (1a), ψ-bufarenogin (1b),[9] and 3- oxo- ψ-bufarenogin (1c). The biotransformation processes consists of a main reaction whereas the dehydrogenation of the 3-hydroxyl group takes place. This process is followed by isomerization.[10]

The different metabolites obtained from the biotransformation of arenobufagin by Alternaria alternata

Similar forms

Arenobufagin is a derivative of the so-called bufadienolides, where it also has a steroid structure. A characteristic of bufadienolides is that they all contain two double bonds in the lactone ring.

Symptoms

Circulatory system

Arenobufagin works like Cardiac glycosides. It inhibits the

sodium-potassium pump
because it stabilises the E2-P transition state, in which the pump is inactive. Second membrane transporter NCX is responsible for 3Na/Ca transport, if the Na-K-Pump does not function correctly the Ca concentration inside the cell will rise and this will cause heart failure. However, in experiments concerning the anti-cancer effects of arenobufagin in mice, no negative effects where found.

Digestive system

Arenobufagin has shown to cause appoptose in hepatocellular carcinoma cells in mice, although this method is not used to cure hepatocellular carcinoma in modern human medicine.

Structure-activity relationships

There is a rather large homology in structure between arenobufagin and

sodium potassium pump
like arenobufagin. The specific steroidic structure binds to the pump in a way it inhibits the process of pumping potassium into the cell and sodium out of the cell. The exact way of binding to the Na-K-Pump is not yet documented.

  • Structure of arenobufagin
    Structure of arenobufagin
  • Structure of a cardiac glycoside, proscillaridin
    Structure of a cardiac glycoside, proscillaridin

Toxicity

Acute toxicity

Although a low dosis of arenobufagin can be used as a medicine of heart rate problems, a high dose can lead to acute heart problems and even death. Arenobufagin is also toxic for hepatocellular carcinoma cells, which is a positive result for the body.

Chronic exposure

Toxicity because of chronic exposure was not clearly documented thus far. However it is discussed that the chronic exposure to this compound can cause the development of

tumors
.

See also

References

  1. PMID 3127947
  2. PMID 8223897
  3. PMID 22305746
    .
  4. ^ Zhang, D. M., et al. (2013). "Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway." Carcinogenesis 34(6): 1331-1342.
  5. ^ Li M, Wu S, Liu Z, Zhang W, Xu J, Wang Y, Liu J, Zhang D, Tian H, Li Y, Ye W. (2012). “Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGFmediated angiogenesis through suppression of VEGFR-2 signaling pathway.” Biochemical Pharmacology. 83, 1251–1260
  6. ^ Tang,J. et al. (2008) “Research progress on clinical application of venenum bufonis preparation as antineoplastic drug.” China Pharmaceuticals, 17, 15-16.
  7. ^ Li M, Wu S, Liu Z, Zhang W, Xu J, Wang Y, Liu J, Zhang D, Tian H, Li Y, Ye W. (2012). “Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGFmediated angiogenesis through suppression of VEGFR-2 signaling pathway.” Biochemical Pharmacology. 83, 1251–1260
  8. ^ Zhang, D. M., et al. (2013). "Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway." Carcinogenesis 34(6): 1331-1342.
  9. PMID 20432230
    .
  10. S2CID 84624677
    .
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