Author Archives: Carlos Torres

Differential Activities of the Botanical Extract PBI-05204 and Oleandrin on Innate Immune Functions under Viral Challenge Versus Inflammatory Culture Conditions

The Nerium oleander extract PBI 05204 (PBI) and its cardiac glycoside constituent oleandrin have direct anti-viral properties. Their effect on the immune system, however, is largely unknown. We used an in vitro model of human peripheral blood mononuclear cells to document effects under three different culture conditions: normal, challenged with the viral mimetic polyinosinic:polycytidylic acid Poly I:C, and inflamed by lipopolysaccharide (LPS). Cells were evaluated for immune activation marks CD69, CD25, and CD107a, and culture supernatants were tested for cytokines. Both PBI and oleandrin directly activated Natural Killer (NK) cells and monocytes and triggered increased production of cytokines. Under viral mimetic challenge, PBI and oleandrin enhanced the Poly I:C-mediated immune activation of monocytes and NK cells and enhanced production of IFN-γ. Under inflammatory conditions, many cytokines were controlled at similar levels as in cultures treated with PBI and oleandrin without inflammation.

Discovery of senolytics using machine learning

Cellular senescence is a stress response involved in ageing and diverse disease processes including cancer, type-2 diabetes, osteoarthritis and viral infection. Despite growing interest in targeted elimination of senescent cells, only few senolytics are known due to the lack of well-characterised molecular targets. Here, we report the discovery of three senolytics using cost-effective machine learning algorithms trained solely on published data. We computationally screened various chemical libraries and validated the senolytic action of ginkgetin, periplocin and oleandrin in human cell lines under various modalities of senescence. The compounds have potency comparable to known senolytics, and we show that oleandrin has improved potency over its target as compared to best-in-class alternatives.

The botanical drug PBI-05204, a supercritical CO2 extract of Nerium oleander, sensitizes alveolar and embryonal rhabdomyosarcoma to radiotherapy in vitro and in vivo

Treatment of rhabdomyosarcoma (RMS), the most common a soft tissue sarcoma in childhood, provides intensive multimodal therapy, with radiotherapy (RT) playing a critical role for local tumor control. However, since RMS efficiently activates mechanisms of resistance to therapies, despite improvements, the prognosis remains still largely unsatisfactory, mainly in RMS expressing chimeric oncoproteins PAX3/PAX7-FOXO1, and fusion-positive (FP)-RMS. Cardiac glycosides (CGs), plant-derived steroid-like compounds with a selective inhibitory activity of the Na+/K+-ATPase pump (NKA), have shown antitumor and radio-sensitizing properties. Herein, the therapeutic properties of PBI-05204, an extract from Nerium oleander containing the CG oleandrin already studied in phase I and II clinical trials for cancer patients, were investigated, in vitro and in vivo, against FN- and FP-RMS cancer models.

Suppression of the ‘stemness’ of glioblastoma stem cells

Glioblastoma multiforme (GBM) is an aggressive form of primary brain neoplasm that has a poor prognosis and is resistant to conventional treatment. There is a great need to develop new strategies to improve the outcome of this disease. PBI-05204, a supercritical CO2 Nerium oleander extract containing cardiac glycosides, such as oleandrin, has been tested in Phase I and II clinical trials for treatment of solid tumors.

Efficacy of oleandrin and PBI-05204 against bovine viruses of importance to commercial cattle health

Bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), and bovine coronavirus (BCV) threaten the productivity of cattle worldwide. Development of therapeutics that can control the spread of these viruses is an unmet need. The present research was designed to explore the in vitro antiviral activity of the Nerium oleander derived cardiac glycoside oleandrin and a defined N. oleander plant extract (PBI-05204) containing oleandrin.

A Role for Cardiac Glycosides in GBM Therapy

There is a pressing need for new effective therapeutic strategies to treat glioblastoma (GBM). Cardiac glycoside compounds consisting of both cardenolides and bufadienolides have been shown to possess potent activity against GBM cell lines and in vivo GBM tumors. In addition, recent research has shown that certain cardiac glycoside compounds contribute to an additive and even synergistic manner with the standard of care GBM treatments such as radiotherapy and chemotherapy. Finally, the finding that cardiac glycosides may offer a unique role in the control of GBM stem cells offers hope for better therapeutic outcomes in treating this deadly form of brain cancer.