Colorectal cancer afflicts around 150,000 Americans, and one million people worldwide, annually. Significant progress has been made in understanding its molecular carcinogenesis and in early detection. Surgery, chemotherapy, and radiation have remained the mainstays of therapy, but unfortunately, colorectal cancer remains the second leading cause of death from cancer in the United States, and patient survival has improved only modestly during the past two decades.
Natural killer (NK) cells are being increasingly considered in immunotherapy for cancers, including colorectal cancer. NK cells express the NKG2D receptor that can recognize NKG2D ligands (NKG2DLs) on tumor cells. The lack of NKG2DL expression on tumor cells has been shown to be associated with poor prognosis in patients with colon cancer. Thus, up regulated expression of these ligands could aid in cancer treatment.
Researchers at St. Jude discovered that specific retinoid receptors, specifically RXR γ agonists and RXR α antagonists, can be used as cancer therapies. They found spironolactone (SPIR), a RXR γ agonist and FDA-approved diuretic drug with a long-term safety profile, can up-regulate NKG2DL expression in multiple colon cancer cell lines, which enhances tumor elimination by NK cells. Although SPIR is a known aldosterone antagonist, its antitumor effects work through a novel RXR γ pathway, which is independent of the mineralocorticoid receptor pathway. SPIR can also up-regulate the expression of metastatic suppressor genes, thereby reducing tumor cell invasiveness. These results show SPIR is a potent anticancer agent that favorably regulates NKG2DL and metastasis-suppressor gene expression, enhancing tumor susceptibility to NK cell cytotoxicity and inhibiting metastasis.
These results strongly support the use of SPIR not only for colon cancer prevention and therapy, but also as a head and neck, prostate, liver, and smooth muscle cancer treatment. This discovery also may aid in the development of other RXR γ agonists, as well as RXR α antagonists; which could prove even more effective than SPIR.
Colorectal cancer, NK cells, immunotherapy, NKG2D ligand (NKG2DL), spironolactone (SPIR), retinoid X receptor γ (RXR γ); head/neck, prostate, liver, and smooth muscle cancer
Granted Patents or Published Applications
US Patent pending, PCT published as WO 2015/061686 April 30, 2015.
Related Scientific References
Leung, et al., Modulation of NKG2D ligand expression and metastasis in tumors by spironolactone via RXR γ activation, J. Exp. Med. 2013 Vol. 210 No. 12 2675-2692 www.jem.org/cgi/doi/10.1084/jem.20122292
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