Method of sensitizing cancer cells to the cytotoxic effects of death receptor ligands in cancer treatment

Inventors

Sayers, Thomas Joseph • Booth, Nancy Lynn • Henrich, Curtis J. • Brooks, Alan David • Gustafson, Kirk R. • Erickson, Karen L.

Assignees

US Department of Health and Human Services

Abstract

Disclosed is a method of enhancing the response of cancer cells in a mammal to treatment with a death receptor ligand, which method comprises contacting the cancer cells with a death receptor ligand in conjunction with an effective amount of a compound described herein, for example, a cucurbitacin (I) or a withanolide (II). Also disclosed is a method of inducing apoptosis in cancer cells in a mammal, comprising contacting the cancer cells with a compound described herein, for example, a cucurbitacin (I) or a withanolide (II) and also contacting the cancer cells with a death receptor ligand, whereby apoptosis is induced in the cancer cells.

Core Innovation

The invention provides a method of synergistically enhancing the response of cancer cells in a mammal to treatment with a death receptor ligand by administering an effective amount of a sensitizer compound in conjunction with the death receptor ligand. The sensitizers are specific compounds including cucurbitacin derivatives of formula (I), withanolide derivatives of formula (II), or compounds of Formulas (III), (IV), or (V). This method enhances the response of the cancer cells more than the additive effects of the individual components and can trigger apoptosis in cells resistant to death receptor ligands.

The method can involve contacting the cancer cells with the sensitizer and the death receptor ligand simultaneously or sequentially, with various formulations and administration routes described. The invention describes the ability of certain compounds, such as cucurbitacin B, withanolides E and S, and others, to sensitize cancer cells to death receptor ligands like TRAIL, resulting in increased apoptosis mediated through caspase activation manifesting a synergistic therapeutic effect.

The problem being solved addresses the resistance of many cancer cells to death receptor ligands such as TRAIL, which, although promising for selectively inducing apoptosis in cancer cells with low toxicity, is often ineffective alone in resistant cancers. There exists an unmet need for sensitizers that can enhance cancer cell responsiveness to death receptor ligand treatment, thereby overcoming resistance and enhancing apoptosis induction with reduced side effects compared to traditional chemotherapies.

Claims Coverage

The patent contains two main independent claims covering methods of enhancing cancer cell response and inducing apoptosis using combinations of sensitizer compounds and death receptor ligands.

The independent claims cover methods using specific sensitizer compounds with death receptor ligands to synergistically enhance response and induce apoptosis in resistant cancer cells, encompassing various cucurbitacin and withanolide derivatives and certain other specified compounds, focusing on effective combinations for cancer treatment.

Stated Advantages

Documented Applications