This is a follow up to the recent post on Oleander which has been turned off.
Clinical Summary
Nerium oleander is an ornamental shrub native to northern Africa, the eastern Mediterranean basin, and Southeast Asia. It is used in traditional medicine to treat hemorrhoids, ulcers, leprosy, and as an abortifacient. The leaf is poisonous because of oleandrin, a cardiac glycoside with structure and actions similar to those of digoxin, and both exert their effects by inhibiting membrane enzyme Na+, K+ -ATPase (1).
Most studies have focused on the anticancer activities of oleandrin because of its apoptotic effects in various cancer cell lines (2)(3)(4)(5)(6)(7)(8). It also increases sensitivity of PC-3 human prostate cells to radiotherapy (9) and reduces gentamycin toxicity (10). A study in glioma models suggest potential activity (27). In other studies, oleandrin demonstrated neuroprotective activity (11) and reduced infectivity of the HIV virus (24).
A hot water extract of the plant, known as Anvirzel™, has been developed as a potential treatment for cancer, AIDS, and congestive heart failure. It consists of a mixture of oleandrin and the glycone oleandrigenin. Experiments suggest that a combination of Anvirzel and cisplatin may be more effective than cisplatin monotherapy (28). In an earlier study, Anvirzel appeared safe in humans when injected intramuscularly, although adverse effects such as injection site pain, fatigue, and other GI symptoms were reported (12).
Anvirzel™ is not an approved cancer treatment in the United States. Until more data regarding its efficacy and toxicity are available, this product should not be used outside of clinical trials.
Mechanism of Action
Oleandrin may slow tumor growth by inhibiting the membrane enzyme Na+, K+ -ATPase (1), especially in cells that have higher ratio of alpha 3 to alpha 1 isoform expression (13). It improves cellular export of fibroblast growth factor-2 (FGF-2) (4). Oleandrin also induces apoptosis through NF-kB suppression (2)(15). It was shown to selectively sensitize lung cancer cells to apoptosis-inducing ligand Apo2L/TRAIL. This was accompanied by upregulation of death receptors 4 (DR4) and 5 (DR5) at both the RNA and protein levels (16).
Other proposed mechanisms include the formation of superoxide radicals that cause tumor cell injury via mitochondrial disruption (7), inhibition of interleukin-8 that mediates tumorigenesis (17), activation of caspase-3 (9), induction of tumor cell autophagy (6), and inhibition of Pgp (8).
In a recent study, PBI-05204, an extract of Nerium Oleander, inhibited proliferation of the Panc-1 tumor cells in part, via downregulation of PI3k/Akt and mTOR pathways (26).
Warnings
Unprocessed leaves from the Nerium oleander plant are highly toxic.
Contraindications
Patients with hypercalcemia, hypokalemia, bradycardia, ventricular tachycardia, or heart failure should not use this product (12).
Adverse Reactions
Common (Raw botanical)
Consumption of even one Nerium oleander leaf can be fatal (25). Onset of toxicity occurs several hours following consumption. Symptoms include vomiting, abdominal pain, cyanosis, hypotension, hypothermia, vertigo, respiratory paralysis and death. These symptoms can occur at a serum oleandrin levels between 1.0 and 2.0 ng/mL (19).
With Anvirzel™, pain at injection site, fatigue, transient erythema, nausea, vomiting and diarrhea.
Case Reports
Death of an adult diabetic man: Due to consumption of oleander leaves. Oleandrin levels in the blood were roughly 10 ng/mL (20).
Death suspected from daily intramuscular injections: In a 43-year-old patient with metastatic synovial sarcoma of the knee who used daily intramuscular injections of Nerium oleander extract for 2 months. Symptoms included nausea, vomiting, severe stomach pain and bloating followed by a gradual reduction in liver enzymes and cardiopulmonary arrest (21).
Accidental poisoning: In a woman who attempted to self-medicate for thyroid disease (14).
Herb-Drug Interactions
Digoxin: Theoretically, cardiac glycosides in Nerium oleander may have an additive effect with digoxin, causing toxicity.
P-glycoprotein (P-gp) substrates: Oleander leaf extract inhibits P-gp and may increase the blood levels of substrate drugs. (8)
References
Lin Y, Ho DH, Newman RA. Human tumor cell sensitivity to oleandrin is dependent on relative expression of Na+, K+ -ATPase subunitst. J Exp Ther Oncol. 2010;8(4):271-286.
Manna SK, Sah NK, Newman RA, et al. Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. Cancer Res. Jul 15 2000;60(14):3838-3847.
Pathak S, Multani AS, Narayan S, et al. Anvirzel, an extract of Nerium oleander, induces cell death in human but not murine cancer cells. Anticancer Drugs. Jul 2000;11(6):455-463.
Smith JA, Madden T, Vijjeswarapu M, et al. Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. Biochemical pharmacology. Aug 15 2001;62(4):469-472.
Felth J, Rickardson L, Rosen J, et al. Cytotoxic effects of cardiac glycosides in colon cancer cells, alone and in combination with standard chemotherapeutic drugs. J Nat Prod. Nov 2009;72(11):1969-1974.
Newman RA, Kondo Y, Yokoyama T, et al. Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr Cancer Ther. Dec 2007;6(4):354-364.
Newman RA, Yang P, Hittelman WN, et al. Oleandrin-mediated oxidative stress in human melanoma cells. J Exp Ther Oncol 2006;5(3):167-181.
Turan N, Akgun-Dar K, Kuruca SE, et al. Cytotoxic effects of leaf, stem and root extracts of Nerium oleander on leukemia cell lines and role of the p-glycoprotein in this effect. J Exp Ther Oncol 2006;6(1):31-38.
Nasu S, Milas L, Kawabe S, et al. Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process. Cancer Lett. Nov 28 2002;185(2):145-151.
Emanuele E, Olivieri V, Aldeghi A, et al. Topical administration of oleandrin could protect against gentamicin ototoxicity via inhibition of activator protein-1 and c-Jun N-terminal kinase. Med Hypotheses. 2007;68(3):711.
Dunn DE, He DN, Yang P, et al. In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models. J Neurochem. Nov 2011;119(4):805-814.
Mekhail T, Kaur H, Ganapathi R, et al. Phase 1 trial of Anvirzel in patients with refractory solid tumors. Invest New Drugs. Sep 2006;24(5):423-427.
Yang P, Menter DG, Cartwright C, et al. Oleandrin-mediated inhibition of human tumor cell proliferation: importance of Na,K-ATPase alpha subunits as drug targets. Mol Cancer Ther. Aug 2009;8(8):2319-2328.
Bavunoglu I, Balta M, Turkmen Z. Oleander Poisoning as an Example of Self-Medication Attempt. Balkan Med J. Sep 2016;33(5):559-562.
Afaq F, Saleem M, Aziz MH, et al. Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin. Toxicol Appl Pharmacol. Mar 15 2004;195(3):361-369.
Frese S, Frese-Schaper M, Andres AC, et al. Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5. Cancer Res. Jun 1 2006;66(11):5867-5874.
Manna SK, Sreenivasan Y, Sarkar A. Cardiac glycoside inhibits IL-8-induced biological responses by downregulating IL-8 receptors through altering membrane fluidity. J Cell Physiol. Apr 2006;207(1):195-207.
Ni D, Madden TL, Johansen M, et al. Murine pharmacokinetics and metabolism of oleandrin, a cytotoxic component of Nerium oleander. J Exp Ther Oncol Sep-Oct 2002;2(5):278-285.
Pietsch J, Oertel R, Trautmann S, et al. A non-fatal oleander poisoning. Int J Legal Med. Jul 2005;119(4):236-240.
Wasfi IA, Zorob O, Al katheeri NA, et al. A fatal case of oleandrin poisoning. Forensic Sci Int. Aug 6 2008;179(2-3):e31-36.
Altan E, Bitik B, Kalpakci Y, et al. Probable hepatotoxicity related to Nerium oleander extract in a patient with metastatic synovial sarcoma of the knee. J Altern Complement Med. Feb 2009;15(2):113.
Datta P, Dasgupta A. Interference of oleandrin and oleandrigenin in digitoxin immunoassays: minimal cross reactivity with a new monoclonal chemiluminescent assay and high cross reactivity with the fluorescence polarization assay. Ther Drug Monit. Aug 1997;19(4):465-469.
Dasgupta A, Risin SA, Reyes M, et al. Rapid detection of oleander poisoning by Digoxin III, a new Digoxin assay: impact on serum Digoxin measurement. Am J Clin Pathol. Apr 2008;129(4):548-553.
Singh S, Shenoy S, Nehete PN, et al.Nerium oleander derived cardiac glycoside oleandrin is a novel inhibitor of HIV infectivity. Fitoterapia. 2013 Jan;84:32-9.
Papi L, Luciani AB, Forni D, Giusiani M. Unexpected double lethal oleander poisoning. Am J Forensic Med Pathol. 2012 Mar;33(1):93-7.
Pan Y, Rhea P, Tan L, et al. PBI-05204, a supercritical CO2 extract of Nerium oleander, inhibits growth of human pancreatic cancer via targeting the PI3K/mTOR pathway. Invest New Drugs. 2015 Apr;33(2):271-9
Garofalo S, Grimaldi A, Chece G, et al. The Glycoside Oleandrin Reduces Glioma Growth with Direct and Indirect Effects on Tumor Cells. J Neurosci. Apr 5 2017;37(14):3926-3939.
Apostolou P, Toloudi M, Chatziioannou M, et al. Anvirzel in combination with cisplatin in breast, colon, lung, prostate, melanoma and pancreatic cancer cell lines. BMC Pharmacol Toxicol. Mar 25 2013;14:18.
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