oleandrin and Pancreatic-Neoplasms

This trial evaluating a novel plant extract, PBI-05204, did not meet its primary endpoint of overall survival but did show signals of efficacy in heavily pretreated mPDA. PBI-05204 was generally well tolerated, with the most common side effects related to treatment being vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Additional trials are needed to explore the role of PBI-05204 in cancer treatment.. Survival for metastatic pancreatic ductal adenocarcinoma (mPDA) is dismal, and novel agents are needed. PBI-05204 is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a cardiac glycoside that has demonstrated antitumor activity in various tumor cell lines with a mechanism involving inhibition of Akt phosphorylation and through downregulation of mTOR.. A phase II, single-arm, open-label study to determine the efficacy of PBI-05204 in patients with refractory mPDA therapy was conducted. The primary endpoint was overall survival (OS), with the hypothesis that 50% of patients would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Patients received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or patient withdrawal. Radiographic response was assessed every two cycles.. Forty-two patients were enrolled, and 38 were analyzed. Ten patients were alive at 4.5 months (26.3%) with a median PFS of 56 days. One objective response (2.6%) was observed for 162 days. Grade ≥ 3 treatment-emergent adverse events occurred in 63.2% of patients with the most common being fatigue, vomiting, nausea, decreased appetite, and diarrhea.. PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate a role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy and radiotherapy. A randomized phase II trial is currently being designed.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Heterocyclic Compounds, 4 or More Rings; Humans; Pancreatic Neoplasms

Platinum derivatives are used widely for the treatment of many cancers. However, the toxicity that is observed makes imperative the need for new drugs, or new combinations. Anvirzel™ is an extract which has been demonstrated with experimental data that displays anticancer activity. The aim of the present study is to determine whether the combination of Cisplatin and Anvirzel™ has a synergistic effect against different types of cancer.. To measure the efficacy of treatment with Cisplatin and Anvirzel™, methyl-tetrazolium dye (MTT) chemosensitivity assays were used incorporating established human cancer cell lines. Measurements were performed in triplicates, three times, using different incubation times and different concentrations of the two formulations in combination or on their own. t-test was used for statistical analysis.. In the majority of the cell lines tested, lower concentrations of Anvirzel™ induced a synergistic effect when combined with low concentrations of Cisplatin after an incubation period of 48 to 72 h. The combination of Anvirzel™/Cisplatin showed anti-proliferative effects against a wide range of tumours.. The results showed that the combination of Anvirzel™ and Cisplatin is more effective than monotherapy, even when administered at low concentrations; thus, undesirable toxic effects can be avoided.

Topics: Antineoplastic Agents; Breast Neoplasms; Cardenolides; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; HCT116 Cells; Humans; Male; MCF-7 Cells; Pancreatic Neoplasms; Prostatic Neoplasms; Time Factors

Lipid-soluble cardiac glycosides such as bufalin, oleandrin, and digitoxin have been suggested as potent agents that might be useful as anticancer agents. Past research with oleandrin, a principle cardiac glycoside in Nerium oleander L. (Apocynaceae), has been shown to induce cell death through induction of apoptosis. In PANC-1 cells, a human pancreatic cancer cell line, cell death occurs not through apoptosis but rather through autophagy. Oleandrin at low nanomolar concentrations potently inhibited cell proliferation associated with induction of a profound G(2)/M cell cycle arrest. Inhibition of cell cycle was not accompanied by any significant sub G1 accumulation of cells, suggesting a nonapoptotic mechanism. Oleandrin-treated cells exhibited time- and concentration-dependent staining with acridine orange, a lysosomal stain. Subcellular changes within PANC-1 cells included mitochondrial condensation and translocation to a perinuclear position accompanied by vacuoles. Use of a fluorescent oleandrin analog (BODIPY-oleandrin) revealed co-localization of the drug within cell mitochondria. Damaged mitochondria were found within autophagosome structures. Formation of autophagosomes was confirmed through electron microscopy and detection of green fluorescent protein-labeled light chain 3 association with autophagosome membranes. Also observed was a drug-mediated inhibition of pAkt formation and up-regulation of pERK. Transfection of Akt into PANC-1 cells or inhibition of pERK activation by MAPK inhibitor abrogated oleandrin-mediated inhibition of cell growth, suggesting that the reduction of pAkt and increased pERK are important to oleandrin's ability to inhibit tumor cell proliferation. The data provide insight into the mechanisms and role of a potent, lipid-soluble cardiac glycoside (oleandrin) in control of human pancreatic cancer proliferation.

Topics: Antineoplastic Agents; Autophagy; Blotting, Western; Cardenolides; Cardiac Glycosides; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Humans; Lipids; Microscopy, Electron, Transmission; Microtubule-Associated Proteins; Mitochondria; Molecular Structure; Organic Chemicals; Pancreatic Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Solubility; Transfection