Rottlerin

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

Rottlerin
Clinical data
Other namesMallotoxin
Identifiers
PubChem CID
ChemSpider
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.001.270
Chemical and physical data
FormulaC30H28O8
Molar mass516.546 g·mol−1
3D model (JSmol)

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.[1][5][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).[1][6][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.[1][5][6][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]

Sources

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. Soltoff SP (Sep 2007). "Rottlerin: an inappropriate and ineffective inhibitor of PKCdelta". Trends in Pharmacological Sciences. 28 (9): 453–8. doi:10.1016/j.tips.2007.07.003. PMID 17692392.
  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): 37986–92. doi:10.1074/jbc.M105073200. PMID 11498535.
  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): 3884–96. doi:10.1210/en.2002-220259. PMID 12239100.
  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): 5118–25. PMID 12941843.
  5. 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. 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 (2009). "Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation". J Heart Lung Transplant. 28 (10): 1094–1101. doi:10.1016/j.healun.2009.06.011. PMID 19782293.
  8. 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. Sato, T; Saito, T; Saegusa, N; Nakaya, H (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.
  10. Bentzen, BH; Osadchii, O; Jespersen, T; Hansen, RS; Olesen, SP; Grunnet, M (2009). "Activation of big conductance Ca(2 )-activated K ( ) channels (BK) protects the heart against ischemia-reperfusion injury". Pflügers Arch. 457 (5): 979–988. doi:10.1007/s00424-008-0583-5. PMID 18762970.
  11. Sakamoto, K; Ohya, S; Muraki, K; Imaizumi, YA (2008). "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. 108 (1): 135–139. doi:10.1254/jphs.08150sc. PMID 18758135.
  12. Bolli, R; Marban, E (1999). "Molecular and cellular mechanisms of myocardial stunning". Physiol. Rev. 79 (2): 609–634. doi:10.1152/physrev.1999.79.2.609. PMID 10221990.
  13. Kloner, RA; Jennings, RB (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.
  14. Kloner, RA; Jennings, RB (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.
  15. Miura, T; Tanno, M; Sato, T (2010). "Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis". Cardiovasc. Res. 88: 7–15. doi:10.1093/cvr/cvq206. PMID 20562423.
  16. Halestrap, AP; Clarke, SJ; Khaliulin, I (2007). "The role of mitochondria in protection of the heart by preconditioning". Biochim Biophys Acta. 1767 (8): 1007–1031. doi:10.1016/j.bbabio.2007.05.008. PMC 2212780. PMID 17631856.
  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. Gschwendt, M; Müller, HJ; Kielbassa, K; Zang, R; Kittstein, W; Rincke, G; Marks, F (Feb 1994). "Rottlerin, a novel protein kinase inhibitor". Biochem Biophys Res Commun. 199 (1): 93–8. doi:10.1006/bbrc.1994.1199. PMID 8123051.
  19. Davies, SP; Reddy, H; Caivano, M; Cohen, P (2001). "Specificity and mechanism of action of some commonly used protein kinase inhibitors". Biochem. J. 351 (Pt 1): 95–105. doi:10.1042/0264-6021:3510095. PMC 1221339. PMID 10998351.
  20. Soltoff, SP (2001). "Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cd tyrosine phosphorylation". J. Biol. Chem. 276: 37986–37992. doi:10.1074/jbc.M105073200. PMID 11498535.
  21. Tapia, JA; Jensen, RT; Garcia-Marin, LJ (Jan 2006). "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. 1763 (1): 25–38. doi:10.1016/j.bbamcr.2005.10.007. PMID 16364465.
  22. 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.
  23. Mitra, R; Kapoor, LD (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.
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