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Combination Therapy with Histone Deacetylase Inhibitors and Lithium Chloride: A Novel Treatment for Carcinoid Tumors

  • Endocrine Tumors
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Abstract

In carcinoid cell lines, the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoyl bis-hydroxamic acid (SBHA) activate the Notch1 pathway, whereas lithium inhibits glycogen synthase kinase-3β (GSK-3β). These compounds limit growth and decrease hormonal secretion in vitro. We hypothesized that lower-dose combination therapy of HDAC inhibitors and lithium chloride could achieve similar growth inhibition to that of the drugs alone. Gastrointestinal and pulmonary carcinoid cells were treated with either VPA or SBHA and lithium chloride for up to 48 hours. Western blot analysis was used to measure the effects on the Notch1 and GSK-3β pathways and the neuroendocrine tumor marker chromogranin A (CgA). Growth was measured by a cellular proliferation assay. With lower-dose combination therapy, a decrease in CgA was observed. The HDAC inhibitors increased the amount of active Notch1 protein, whereas treatment with lithium was associated with inhibition of GSK-3β. Moreover, growth was inhibited with lower-dose combination therapy. Treatment of carcinoid cells with either VPA or SBHA and lithium chloride suppresses the neuroendocrine marker CgA while upregulating Notch1 and inhibiting GSK-3β. This combination effectively reduces growth. Thus, lower-dose combination therapy may be a viable therapeutic approach for carcinoid tumors.

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Acknowledgments

J.T.A. is a Howard Hughes Medical Institute Research Training Fellow and is supported by the University of Wisconsin General Clinical Research Center. Additional support was received from a Research Scholars grant from the American Cancer Society, National Institutes of Health grants CA117117 and CA109053, the George H. A. Clowes Jr. Memorial Research Career Development Award of the American College of Surgeons, a Carcinoid Cancer Foundation research award, the Clinical Investigator’s Award from the Society of Surgical Oncology, and University of Wisconsin Medical School grants (to H.C.); and a Carcinoid Cancer Foundation research award (to M.K.).

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Correspondence to Herbert Chen MD, FACS.

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Adler, J.T., Hottinger, D.G., Kunnimalaiyaan, M. et al. Combination Therapy with Histone Deacetylase Inhibitors and Lithium Chloride: A Novel Treatment for Carcinoid Tumors. Ann Surg Oncol 16, 481–486 (2009). https://doi.org/10.1245/s10434-008-0194-6

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  • DOI: https://doi.org/10.1245/s10434-008-0194-6

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