Therapy Focus

Cancer

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.

PBI Research Summary

The preclinical research and pharmacology studies conducted by Phoenix Biotechnology have to date shown the following with respect to efficacy against malignant diseases:

  • Extracts of Nerium oleander contain potent cardiac glycoside molecules such as oleandrin in addition to other compounds such as betulinic acid with known anticancer properties. READ MORE
  • Oleandrin suppresses activation of NF-κΒ, AP-1 and c-Jun NH2 terminal kinases all of which are important in driving malignant growth.
  • Oleandrin binds to subunits of an enzyme known as Na,K-ATPase. Human malignant cells express a specific 'alpha' subunit while normal cells do not and this is critical in explaining the selectivity of oleandrin with respect to tumor cell death. READ MORE
  • Oleandrin and other components of Nerium oleander readily cross the blood brain barrier and gain entry into brain tissue suggesting their usefulness against CNS malignancies. Ongoing research now has shown strong activity of PBI’s oleander extract against pediatric brain cancer known as glioblastoma multiforme. Samples of actual human brain tumors were grown in mouse brain tissue. Mice were then treated orally with PBI’s plant extract material. Given that there is currently no effective treatment for GBM the activity of PBI’s drug against this type of disease is highly encouraging.
  • Extracts of Nerium oleander produce cell death through a number of specific pathways including apoptosis and autophagy.

Clinical research with PBI-05204:

  • 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.

References


Abstract

2011 ASCO Poster of Phase I trial of PBI-05204

Further Information: See "Product Development" or "Contacts"

cancer cells

Figure above shows a color-enhanced photomicrograph of a Nerium oleander leaf.

References

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