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Rottlerin

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Rottlerin
Clinical data
Other namesMallotoxin
Identifiers
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.001.270 Edit this at Wikidata
Chemical and physical data
FormulaC30H28O8
Molar mass516.546 g·mol−1
3D model (JSmol)
  • O=C(c1c(O)c(c(O)c(c1O)C)Cc3c(O)c(C(=O)\C=C\c2ccccc2)c4OC(/C=C\c4c3O)(C)C)C
  • InChI=1S/C30H28O8/c1-15-24(33)19(27(36)22(16(2)31)25(15)34)14-20-26(35)18-12-13-30(3,4)38-29(18)23(28(20)37)21(32)11-10-17-8-6-5-7-9-17/h5-13,33-37H,14H2,1-4H3/b11-10
  • Key:DEZFNHCVIZBHBI-ZHACJKMWSA-N

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

Effects

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Uncoupler of oxidative phosphorylation

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

Potassium channel opener

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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]

Mallotoxin is also a hERG potassium channel activator.[12]

Role in cardioplegia reperfusion

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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

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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.[13][14][15] 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

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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.[16][17] 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

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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.[1][5][18] There was no oxygen dependent damage found by rottlerin in the study conducted by Clements et al.[5]

Ineffective PKCδ selective inhibitor

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Rottlerin has been reported to be a PKCδ inhibitor.[19] 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][20][21] 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).[1][6][22] 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.[1][5][6][22] 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]

Sources

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The Kamala tree, also known as Mallotus philippensis, grows in Southeast Asia.[19] 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.[23] Other uses include afflictions with the skin, eye diseases, bronchitis, abdominal disease, and spleen enlargement but scientific evidence is not present.[24]

References

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  1. ^ a b c d e f g h Soltoff SP (September 2007). "Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta". Trends in Pharmacological Sciences. 28 (9): 453–458. doi:10.1016/j.tips.2007.07.003. PMID 17692392.
  2. ^ Soltoff SP (October 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): 37986–37992. doi:10.1074/jbc.M105073200. PMID 11498535.
  3. ^ Kayali AG, Austin DA, Webster NJ (October 2002). "Rottlerin inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation". Endocrinology. 143 (10): 3884–3896. doi:10.1210/en.2002-220259. PMID 12239100.
  4. ^ Tillman DM, Izeradjene K, Szucs KS, Douglas L, Houghton JA (August 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): 5118–5125. 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 (September 2011). "Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa channel activation after cold cardioplegic arrest in isolated hearts". Circulation. 124 (11 Suppl): S55–S61. doi:10.1161/CIRCULATIONAHA.110.012112. PMC 3358121. PMID 21911819.
  6. ^ a b c d Zakharov SI, Morrow JP, Liu G, Yang L, Marx SO (September 2005). "Activation of the BK (SLO1) potassium channel by mallotoxin". The Journal of Biological Chemistry. 280 (35): 30882–30887. doi:10.1074/jbc.M505302200. PMID 15998639.
  7. ^ Han JG, Yang Q, Yao XQ, Kwan YW, Shen B, He GW (October 2009). "Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation". The Journal of Heart and Lung Transplantation. 28 (10): 1094–1101. doi:10.1016/j.healun.2009.06.011. PMID 19782293.
  8. ^ a b c Kang SH, Park WS, Kim N, Youm JB, Warda M, Ko JH, et al. (July 2007). "Mitochondrial Ca2 -activated K channels more efficiently reduce mitochondrial Ca2 overload in rat ventricular myocytes". American Journal of Physiology. Heart and Circulatory Physiology. 293 (1): H307–H313. doi:10.1152/ajpheart.00789.2006. PMID 17351070.
  9. ^ a b c d e Sato T, Saito T, Saegusa N, Nakaya H (January 2005). "Mitochondrial Ca2 -activated K channels in cardiac myocytes: a mechanism of the cardioprotective effect and modulation by protein kinase A". Circulation. 111 (2): 198–203. doi:10.1161/01.cir.0000151099.15706.b1. PMID 15623543. S2CID 9912508.
  10. ^ a b Bentzen BH, Osadchii O, Jespersen T, Hansen RS, Olesen SP, Grunnet M (March 2009). "Activation of big conductance Ca(2 )-activated K ( ) channels (BK) protects the heart against ischemia-reperfusion injury". Pflügers Archiv. 457 (5): 979–988. doi:10.1007/s00424-008-0583-5. PMID 18762970. S2CID 25090971.
  11. ^ a b Sakamoto K, Ohya S, Muraki K, Imaizumi Y (September 2008). "A novel opener of large-conductance Ca2 -activated K (BK) channel reduces ischemic injury in rat cardiac myocytes by activating mitochondrial K(Ca) channel". Journal of Pharmacological Sciences. 108 (1): 135–139. doi:10.1254/jphs.08150sc. PMID 18758135.
  12. ^ Zeng H, Lozinskaya IM, Lin Z, Willette RN, Brooks DP, Xu X (November 2006). "Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator". The Journal of Pharmacology and Experimental Therapeutics. 319 (2): 957–962. doi:10.1124/jpet.106.110593. PMID 16928897. S2CID 21096055.
  13. ^ Bolli R, Marbán E (April 1999). "Molecular and cellular mechanisms of myocardial stunning". Physiological Reviews. 79 (2): 609–634. doi:10.1152/physrev.1999.79.2.609. PMID 10221990. S2CID 18283833.
  14. ^ Kloner RA, Jennings RB (December 2001). "Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2". Circulation. 104 (25): 3158–3167. doi:10.1161/hc5001.100039. PMID 11748117. S2CID 52874593.
  15. ^ Kloner RA, Jennings RB (December 2001). "Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1". Circulation. 104 (24): 2981–2989. doi:10.1161/hc4801.100038. PMID 11739316.
  16. ^ Miura T, Tanno M, Sato T (October 2010). "Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis". Cardiovascular Research. 88 (1): 7–15. doi:10.1093/cvr/cvq206. PMID 20562423.
  17. ^ Halestrap AP, Clarke SJ, Khaliulin I (August 2007). "The role of mitochondria in protection of the heart by preconditioning". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1767 (8): 1007–1031. doi:10.1016/j.bbabio.2007.05.008. PMC 2212780. PMID 17631856.
  18. ^ Heinen A, Aldakkak M, Stowe DF, Rhodes SS, Riess ML, Varadarajan SG, Camara AK (September 2007). "Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2 -sensitive K channels". American Journal of Physiology. Heart and Circulatory Physiology. 293 (3): H1400–H1407. doi:10.1152/ajpheart.00198.2007. PMID 17513497. S2CID 20330939.
  19. ^ a b Gschwendt M, Müller HJ, Kielbassa K, Zang R, Kittstein W, Rincke G, Marks F (February 1994). "Rottlerin, a novel protein kinase inhibitor". Biochemical and Biophysical Research Communications. 199 (1): 93–98. doi:10.1006/bbrc.1994.1199. PMID 8123051.
  20. ^ Davies SP, Reddy H, Caivano M, Cohen P (October 2000). "Specificity and mechanism of action of some commonly used protein kinase inhibitors". The Biochemical Journal. 351 (Pt 1): 95–105. doi:10.1042/0264-6021:3510095. PMC 1221339. PMID 10998351.
  21. ^ Soltoff SP (October 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): 37986–37992. doi:10.1074/jbc.M105073200. PMID 11498535.
  22. ^ a b Tapia JA, Jensen RT, García-Marín LJ (January 2006). "Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1763 (1): 25–38. doi:10.1016/j.bbamcr.2005.10.007. PMID 16364465.
  23. ^ Rao VS, Seshadri TR (1947). "Kamala dye as an anthelmintic". Proceedings of the Indian Academy of Sciences. 26 (3): 178–181. doi:10.1007/BF03170871. S2CID 81455004.
  24. ^ Mitra R, Kapoor LD (November 1976). "Kamala--the national flower of India--its ancient history and uses in Indian medicine". Indian Journal of History of Science. 11 (2): 125–132. PMID 11610202.
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