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Rottlerin

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Rottlerin
File:Rottlerin.svg
Systematic (IUPAC) name
(E)-1-[6-[(3-acetyl-2,4,6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2,2-dimethylchromen-8-yl]-3-phenylprop-2-en-1-one
Clinical data
Identifiers
PubChem CID 5281847
ChemSpider 4445144
ChEBI CHEBI:8899
Synonyms Mallotoxin
Chemical data
Formula C30H28O8
516.53852 g/mol

Rottlerin (mallotoxin) is a polyphenol natural product isolated from the asian tree Mallotus philippensis. Rottlerin displays a complex spectrum of pharmacology.[1]

Effects

Uncoupler of oxidative phosphorylation

Rottlerin has been shown to be an uncoupler of mitochondrial oxidative phosphorylation.[2][3][4]

Potassium channel opener

Rottlerin is a potent large conductance potassium channel (BKCa++) opener.[5] BKCa++ is found in the inner mitochondrial membrane of cardiomyocytes.[6] Opening these channels is beneficial for post-ischemic changes in vasodilation.[7] Other BKCa++ channel openers are reported to limit the mitochondrial calcium overload due to ischemia.[8][9] Rottlerin is also capable of reducing oxygen radical formation.[1]

Other BKCa++ channel openers (NS1619, NS11021 and DiCl-DHAA) have been reported to have cardio-protective effects after ischemic-reperfusion injury.[9][10][11] There were reductions in mitochondrial Ca++ overload, mitochondrial depolarization, increased cell viability and improved function in the whole heart.[9][10][11]

Role in cardioplegia reperfusion

Clements et al.[5] reported that rottlerin improves the recovery of isolated rat hearts perfused with buffer after cold cardioplegic arrest. A majority of patients recover but some develop a cardiac low-output syndrome attributable in part to depressed left ventricular or atrial contractility, which increases chance of death.[5]

Contractility and vascular effects

Rottlerin increases in isolated heart contractility independent of its vascular effects, as well as enhanced perfusion through vasomotor activity.[5] The activation of BKCa++ channels by rottlerin relaxes coronary smooth muscle and improves myocardial perfusion after cardioplegia.[5]

Myocardial stunning is associated with oxidant radical damage and calcium overload.[5] Contractile abnormalities can occur through oxidant-dependent damage and also through calcium overload in the mitochondria resulting in mitochondrial damage.[12][13][14] BKCa++ channels reside in the inner mitochondrial membrane[6] and their activation is proposed to increase K+ accumulation in mitochondria.[8][9] This limits Ca2+ influx into mitochondria, reducing mitochondrial depolarization and permeability transition pore opening.[8][9] This may result in less mitochondrial damage and therefore greater contractility since there is a decrease in apoptosis compared to no stimulation of BKCa++ channels.[5]

Akt activation

Rottlerin also enhances the cardioplegia-induced phosphorylation of Akt on the activation residue Thr308.[5] Akt activation modulates mitochondrial depolarization and the permeability transition pore.[15][16] Clements et al[5] found that Akt functions downstream of the BKCa++ channels and its activation is considered beneficial after ischemic-reperfusion injury. It is unclear what the specific role of Akt may play in modulating of myocardial function after rottlerin treatment of cardioplegia.[5] More research needs to be done to examine if Akt is necessary to improve cardiac function when rottlerin is administered.[5]

Antioxidant properties

The antioxidant properties of rottlerin have been demonstrated but it is unclear whether the effects are because of BKCa++ channel opening or an additional mechanism of rottlerin.[5][1][17] There was no oxygen dependent damage found by rottlerin in the study conducted by Clements et al.[5]

Ineffective PKCδ selective inhibitor

Rottlerin has been reported to be a PKCδ inhibitor.[18] PKCδ has been implicated in depressing cardiac function and cell death after ischemia-reperfusion injury as well as promoting vascular smooth muscle contraction and decreasing perfusion.[5] However, the role of rottlerin as a specific PKCδ inhibitor has been questioned. There have been several studies using rottlerin as a PKCδ selective inhibitor based on in vitro studies, but some studies showed it did not block PKCδ activity and did block other kinase and non-kinase proteins in vitro.[1][19][20] Rottlerin also uncouples mitochondria at high doses and results in depolarization of the mitochondrial membrane potential.[1] It was found to reduce ATP levels, activate 5’-AMP-activated protein kinase and affect mitochondrial production of reactive oxygen species (ROS).[6][1][21] It is difficult to say that rottlerin is a selective inhibitor of PKCδ since there are biological and biochemical processes that are PKCδ –independent that may affect outcomes.[5][6][1][21] A proposed mechanism of why rottlerin was found to inhibit PKCδ is that it decreased ATP levels and can block PKCδ tyrosine phosphorylation and activation.[1]

Source

The Kamala tree, also known as Mallotus philippensis, grows in Southeast Asia.[18] The fruit of this tree is covered with a red powder called kamala, and is used locally to make dye for textiles, syrup and used as an old remedy for tape-worm, because it has a laxative effect.[22] Other uses include afflictions with the skin, eye diseases, bronchitis, abdominal disease, and spleen enlargement but scientific evidence is not present.[23]

References

  1. ^ a b c d e f g h Soltoff SP (Sep 2007). "Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta". Trends in Pharmacological Sciences 28 (9). PMID 17692392. doi:10.1016/j.tips.2007.07.003. 
  2. ^ Soltoff SP (Oct 2001). "Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation". The Journal of Biological Chemistry 276 (41). PMID 11498535. doi:10.1074/jbc.M105073200. 
  3. ^ Kayali AG, Austin DA, Webster NJ (Oct 2002). "Rottlerin inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation". Endocrinology 143 (10). PMID 12239100. doi:10.1210/en.2002-220259. 
  4. ^ Tillman DM, Izeradjene K, Szucs KS, Douglas L, Houghton JA (Aug 2003). "Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C". Cancer Research 63 (16). PMID 12941843. 
  5. ^ a b c d e f g h i j k l m n o Clements RT, Cordeiro B, Feng J, Bianchi C, Sellke FW. Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts. Circulation 2011 Sep 13; 124(11 Suppl):S55-61
  6. ^ a b c d Zakharov SI, Morrow JP, Liu G, Yang L, Marx SO. Activation of the BK (SLO1) potassium channel by mallotoxin. J Biol Chem. 2005;280: 30882–30887
  7. ^ Han JG, Yang Q, Yao XQ, Kwan YW, Shen B, He GW. Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation. J Heart Lung Transplant. 2009;28: 1094–1101
  8. ^ a b c Kang SH, Park WS, Kim N, Youm JB, Warda M, Ko JH, Ko EA, Han J. Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes. Am J Physiol Heart Circ Physiol. 2007;293:H307–H313
  9. ^ a b c d e Sato T, Saito T, Saegusa N, Nakaya H. Mitochondrial Ca2+-activated K+ channels in cardiac myocytes: a mechanism of the cardioprotective effect and modulation by protein kinase A. Circulation. 2005;111: 198–203.
  10. ^ a b Bentzen BH, Osadchii O, Jespersen T, Hansen RS, Olesen SP, Grunnet M. Activation of big conductance Ca(2 )-activated K ( ) channels (BK) protects the heart against ischemia-reperfusion injury. Pflugers Arch. 2009;457:979 –988
  11. ^ a b Sakamoto K, Ohya S, Muraki K, Imaizumi YA. Novel opener of largeconductance Ca2 -activated K (BK) channel reduces ischemic injury in rat cardiac myocytes by activating mitochondrial K(Ca) channel. J Pharmacol Sci. 2008;108:135–139
  12. ^ Bolli R, Marban E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev. 1999;79:609–634.
  13. ^ Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2. Circulation. 2001; 104:3158 –3167
  14. ^ Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation. 2001; 104:2981–2989.
  15. ^ Miura T, Tanno M, Sato T. Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis. Cardiovasc Res. 2010;88:7–15.
  16. ^ Halestrap AP, Clarke SJ, Khaliulin I. The role of mitochondria in protection of the heart by preconditioning. Biochim Biophys Acta. 2007; 1767:1007–1031
  17. ^ Heinen A, Aldakkak M, Stowe DF, Rhodes SS, Riess ML, Varadarajan SG, Camara AK. Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2 -sensitive K channels. Am J Physiol Heart Circ Physiol. 2007;293:H1400–H1407.
  18. ^ a b Gschwendt M, Müller HJ, Kielbassa K, Zang R, Kittstein W, Rincke G, Marks F. Rottlerin, a novel protein kinase inhibitor. Biochem Biophys Res Commun. 1994 Feb 28; 199(1):93-8
  19. ^ Davies SP, Reddy H,Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 2001; 351: 95–105
  20. ^ Soltoff SP Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cd tyrosine phosphorylation. J. Biol. Chem. 2001; 276:37986–37992
  21. ^ a b Tapia JA, Jensen RT, Garcia-Marin LJ. Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism. Biochim. Biophys. Acta 2006 Jan;1763(1):25–38. Epub 2005 Nov 18
  22. ^ Rao VS, Seshadri TR. Kamala dye as an anthelmintic. Proceedings of the Indian Academy of Sciences. 1947 Section A; 26(3):178–181.
  23. ^ Mitra R, Kapoor LD. Kamala—the national flower of India—its ancient history and uses in Indian medicine. Indian Journal of History of Science.1976; 11(2):125–132.