oleandrin and Neoplasms

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

PBI-05204, a Nerium oleander extract (NOE) containing the cardiac glycoside oleandrin, inhibits the α-3 subunit of Na-K ATPase, as well as FGF-2 export, Akt and p70S6K, hence attenuating mTOR activity. This first-in-human study determined the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of PBI-05204 in patients with advanced cancer. Methods Forty-six patients received PBI-05204 by mouth for 21 of 28 days (3 + 3 trial design). Dose was escalated 100% using an accelerated titration design until grade 2 toxicity was observed. Plasma PK and mTOR effector (p70S6K and pS6) protein expressions were evaluated. Results Dose-limiting toxicities (grade 3 proteinuria, fatigue) were observed at dose level 8 (0.3383 mg/kg/day). Common possible drug-related adverse were fatigue (26 patients, 56.5%), nausea (19 patients, 41.3%) and diarrhea (15 patients, 32.6 %). Electrocardiogram monitoring revealed grade 1 atrioventricular block (N = 10 patients) and grade 2 supraventricular tachycardia (N = 1). The MTD was DL7 (0.2255 mg/kg) where no toxicity of grade ≥ 3 was observed in seven patients treated. Seven patients (15%) had stable disease > 4 months. Mean peak oleandrin concentrations up to 2 ng/mL were achieved, with area under the curves 6.6 to 25.5 μg/L*hr and a half-life range of 5-13 h. There was an average 10% and 35% reduction in the phosphorylation of Akt and pS6 in PBMC samples in 36 and 32 patients, respectively, tested between predose and 21 days of treatment. Conclusions PBI-05204 was well tolerated in heavily pretreated patients with advanced solid tumors. The recommended Phase II dose is 0.2255 mg/kg/day.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Cardenolides; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblast Growth Factor 2; Humans; Leukocytes, Mononuclear; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Nerium; NF-kappa B; Phytotherapy; Plant Extracts; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Sodium-Potassium-Exchanging ATPase; TOR Serine-Threonine Kinases

Anvirzel is an aqueous extract of the plant Nerium oleander which has been utilized to treat patients with advanced malignancies. The current study reports a phase 1 trial to determine the maximum tolerated dose (MTD) and safety of Anvirzel in patients with advanced, refractory solid tumors. Patients were randomized to receive this agent by intramuscular injection at doses of 0.1, 0.2, 0.4 ml/m2/day with subsequent patients receiving 0.8 or 1.2 ml/m2/day sequentially. Eighteen patients were enrolled and completed at least one treatment cycle of three weeks. Most patients developed mild injection site pain (78%). Other toxicities included fatigue, nausea, and dyspnea. Traditional dose limiting toxicity was not seen, but the MTD was defined by injection volume as 0.8 ml/m2/day. No objective anti-tumor responses were seen. Anvirzel can be safely administered at doses up to 1.2 ml/m2/day, with the amount administered intramuscularly limited by volume. The recommended phase II dose level is 0.8 ml/m2/day.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Cardenolides; Electrocardiography; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms

Oleandrin is a monomeric compound extracted from leaves and seeds of Nerium oleander. It had been reported that oleandrin could effectively inhibit the growth of human cancer cells. However, the specific mechanisms of the oleandrin-induced anti-tumor effects remain largely unclear. Genomic instability is one of the main features of cancer cells, it can be the combined effect of DNA damage and tumour-specific DNA repair defects. DNA damage plays important roles during tumorigenesis. In fact, most of the current chemotherapy agents were designed to kill cancer cells by inducing DNA damage. In this study, we found that oleandrin was effective to induce apoptosis in cancer cells, and cause rapid DNA damage response, represented by nuclear RPA (Replication Protein A, a single strand DNA binding protein) and γH2AX(a marker for DNA double strand breaks) foci formation. Interestingly, expression of RAD51, a key protein involved in homologous recombination (HR), was suppressed while XRCC1 was up-regulated in oleandrin treated cancer cells. These results suggested that XRCC1 may play a predominant role in repairing oleandrin-induced DNA damage. Collectively, oleandrin may be a potential anti-tumor agent by suppressing the expression of Rad51.

Topics: A549 Cells; Apoptosis; Blotting, Western; Cardenolides; Cell Line; Cell Line, Tumor; DNA Damage; DNA Repair; Histones; Humans; Neoplasms; Rad51 Recombinase; RNA Interference; X-ray Repair Cross Complementing Protein 1

The membrane enzyme Na+, K+ -ATPase is known to help maintain ion homeostasis in mammalian cells. Newly identified functions of this enzyme suggest that inhibition of Na+, K+ -ATPase by cardiac glycosides may be useful to patients with cancer. Twelve human tumor cell lines were chosen to examine determinants of human tumor cell sensitivity to cardiac glycosides. In vitro cell culture models of human glioma HF U251 and U251 cells as well as human parental and modified melanoma BRO cells were also included in these studies. Data derived from both models and twelve tumor cell lines indicated that high expression of Na+, K+ -ATPase alpha 1 isoform in the presence of low alpha 3 expression correlated with increased resistance to inhibition of cell proliferation by cardiac glycosides such as oleandrin, ouabain and bufalin. Interestingly, increased expression of Na+, K+ -ATPase alpha 1 and therefore total Na+, K+ -ATPase activity is associated with increased cellular levels of glutathione. The altered enzyme activity and glutathione content were associated with a delayed and diminished release of cytochrome c and caspase activation. Additionally, an increased colony-forming ability was noted in cells with high levels of Na+, K+ -ATPase alpha 1 expression, suggesting that Na+, K+ -ATPase alpha 1 isoform may be actively involved in tumor growth and cell survival. Its inhibition by cardiac glycosides may provide a strategy for effective cancer therapy.

Topics: Cardenolides; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cytochromes c; Enzyme Activation; Glutathione; Humans; Neoplasms; Protein Subunits; Sodium-Potassium-Exchanging ATPase

Chemotherapeutic agent is characterized by its concentration in tumor cells with minimum side effects. Oleandrin, a polyphenolic cardiac glycoside is known to induce apoptosis in tumor cells. However, no report is available on its efficacy in primary cells. In this report we are providing the evidence that oleandrin induces apoptosis, not necrosis in tumor cells but not in primary cells like peripheral blood mononuclear cells (PBMC) and neutrophils. Oleandrin inhibited NF-kappaB activation in tumor cells but not in primary cells. It induced cell death in NF-kappaB-overexpressed tumor cells. Oleandrin induced Fas expression thereby inducing apoptosis in tumor cells but not in primary cells. Dominant negative FADD inhibited oleandrin-induced cell death in tumor cells. Overall, these results suggest that oleandrin mediates apoptosis in tumor cells by inducing Fas but not in primary cells indicating its potential anti-cancer property with no or slight side effect.

Topics: Antineoplastic Agents; Apoptosis; Blood Cells; Cardenolides; Cell Line, Tumor; Cells, Cultured; fas Receptor; Gene Expression Regulation; Humans; Neoplasms; NF-kappa B