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
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

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]

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

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.[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

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

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

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

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

  1. 1 2 3 4 5 6 7 8 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. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 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. 1 2 3 4 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. 1 2 3 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. 1 2 3 4 5 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. 1 2 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. 1 2 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. 1 2 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. 1 2 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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