The class of steroid-like compounds designated 'cardiac glycosides' includes well known clinically useful, plant-derived drugs like digoxin and digitoxin. Their continued use and efficacy in treatment of congestive heart failure and as anti-arrythmic agents is well appreciated. Less well known, however, is the emerging role of this category of compounds in the prevention and/or treatment of proliferative diseases such as cancer. New findings within the past several years have revealed that certain cardiac glycosides are involved in complex signal transduction mechanisms (sending life or death signals from the cell membrane to the cell nucleus). As such, these compounds represent a promising new form of cancer chemotherapy.
Research sponsored by Phoenix Biotechnology has shown that novel, patented extracts of Nerium oleander are selectively toxic to human but not rodent tumor cells. More importantly, this discovery led to research showing that oleander extracts were also selectively toxic to human malignant cells but not human normal cells. The promise of PBI's main botanical drug (PBI-05204) appears great as it has shown activity against otherwise difficult to treat human cancers such as melanoma, prostate and breast cancers as well as certain hematologic malignancies. Based on these studies and related promising discoveries Phoenix Biotechnology launched a Phase I clinical study of PBI-05204 at the University of Texas M. D. Anderson Cancer Center. That trial has now been completed and the encouraging results are discussed below.
Recent independent research conducted at both the Houston Medical Center as well as in Italy at the University of A’Quila has provided highly encouraging data in nude (immunocompromised) mice with human brain tumors. When combined with both radiation and chemotherapy such as temozolamide) PBI-05204 significantly extended the lives of mice in this combination treatment strategy. Given the fact that glioblastoma is a very difficult to treat form of brain cancer we think that this adjuvant use of PBI-05204 will be a valuable treatment strategy.
The preclinical research and pharmacology studies conducted by Phoenix Biotechnology have to date shown the following with respect to efficacy against malignant diseases:
PBI-05204 can be administered safely to patients with advanced cancers without exhibiting any evidence of cardiac toxicity.
In a Phase I trial of PBI-05204 conducted at the University of Texas M. D. Anderson Cancer Center (Houston, TX) it was observed that the drug produced a series of stable responses and partial remissions in heavily pretreated cancer patients which is encouraging at this step of development.
In recent Phase II trials of PBI-05204 against heavily pretreated pancreatic cancer patients, administration of PBI-05204 again was shown to be safe and, in addition, to produce some stable disease as well as partial responses.
Continued examination of the anticancer efficacy of PBI-05204 against tumor 'spheroids' obtained from tumor biopsies resected from cancer patients but which are grown in culture are also very promising. This constitutes an ex vivo "Phase II" series of studies pointing the direction for productive future clinical trials involving specific malignant diseases.
Further Information: See "Product Development" or "Contacts"
Figure above shows a color-enhanced photomicrograph of a Nerium oleander leaf.
Human tumor cell sensitivity to oleandrin is dependent on relative expression of Na+, K+ -ATPase subunits. Lin Y, Ho DH, Newman RA. J Exp Ther Oncol. 2010;8(4):271-86. PMID: 21222360
Oleandrin-mediated inhibition of human tumor cell proliferation: importance of Na,K-ATPase alpha subunits as drug targets. Yang P, Menter DG, Cartwright C, Chan D, Dixon S, Suraokar M, Mendoza G, Llansa N, Newman RA. Mol Cancer Ther. 2009 Aug;8(8):2319-28. PMID: 19671733
Determinants of human and mouse melanoma cell sensitivities to oleandrin. Lin Y, Dubinsky WP, Ho DH, Felix E, Newman RA. J Exp Ther Oncol. 2008;7(3):195-205. PMID: 19066128
Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Newman RA, Kondo Y, Yokoyama T, Dixon S, Cartwright C, Chan D, Johansen M, Yang P. Integr Cancer Ther. 2007 Dec;6(4):354-64. PMID: 18048883
Oleandrin-mediated oxidative stress in human melanoma cells. Newman RA, Yang P, Hittelman WN, Lu T, Ho DH, Ni D, Chan D, Vijjeswarapu M, Cartwright C, Dixon S, Felix E, Addington C. J Exp Ther Oncol. 2006;5(3):167-81. PMID: 16528968
Murine pharmacokinetics and metabolism of oleandrin, a cytotoxic component of Nerium oleander. Ni D, Madden TL, Johansen M, Felix E, Ho DH, Newman RA. J Exp Ther Oncol. 2002 Sep-Oct;2(5):278-85. PMID: 12416031
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. Smith JA, Madden T, Vijjeswarapu M, Newman RA. Biochem Pharmacol. 2001 Aug 15;62(4):469-72. PMID: 11448457
Composition and preliminary pharmacology studies with Anvirzel: An extract of Nerium oleander. Newman RA, Cisneros A, Felix E, et al. J. Herbal Pharmacotherapy 2001 1(3): 1-16.
Anvirzel, an extract of Nerium oleander, induces cell death in human but not murine cancer cells. Pathak S, Multani AS, Narayan S, Kumar V, Newman RA. Anticancer Drugs. 2000 Jul;11(6):455-63. PMID: 11001386
LC/MS/MS analyses of an oleander extract for cancer treatment. Wang X, Plomley JB, Newman RA, Cisneros A. Anal Chem. 2000 Aug 1;72(15):3547-52. PMID: 10952541
Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. Manna SK, Sah NK, Newman RA, Cisneros A, Aggarwal BB. Cancer Res. 2000 Jul 15;60(14):3838-47. PMID: 10919658
Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. McConkey DJ, Lin Y, Nutt LK, Ozel HZ, Newman RA. Cancer Res. 2000 Jul 15;60(14):3807-12. PMID: 10919654