Differential Effects of Sodium Butyrate and Hexamethylene Bisacetamide on Growth and Secretion of Cultured Human Endocrine Tumor Cells

Abstract

Advanced gastrointestinal endocrine tumors respond poorly to conventional chemotherapy. In this study we examined the effects of two agents that promote cellular differentiation, sodium butyrate and hexamethylene bisacetamide, on the in vitro growth and secretory responses of a human pancreatic carcinoid (BON) and human gastrinoma (PT-2 and PT-SM) cell lines that have been established in our laboratory. We found that both sodium butyrate and hexamethylene bisacetamide strongly inhibited growth of BON, PT-2, and PT-SM cells. With continuous exposure of BON cells to sodium butyrate (2 mmol/L), the doubling time was prolonged, from 60 hours in controls to 156 hours, and saturation density was reduced to 28% that of controls. Hexamethylene bisacetamide (4 mmol/L) reduced saturation density to 37% that of controls in BON cells and prolonged the doubling time, from 60 hours to 103 hours. Antiproliferative effects of similar magnitudes were observed in the gastrinoma cell lines. In contrast, differential effects were produced on amine biosynthesis in BON cells; sodium butyrate stimulated levels of 5-hydroxytryptamine in the cells, whereas hexamethylene bisacetamide caused a profound dose-dependent inhibition of amine biosynthesis. The significant antiproliferative activity of sodium butyrate and hexamethylene bisacetamide and the inhibitory effects of hexamethylene bisacetamide on amine biosynthesis warrant evaluation of these agents or analogues for treatment of metastatic carcinoid and gastrinoma.

Establishment of the First Well-differentiated Human Pancreatic Neuroendocrine Tumor Model

“…Given that both cell lines have been in use for more than 25 years, it appears likely that the cells have acquired a more malignant phenotype in culture. Although the currently detected doubling times of 36 and 38 hours for BON and QGP-1 cells, respectively, are higher than the originally reported doubling times of 60 hours (BON) (22) and 84 hours (QGP-1; ref. 23), these cells proliferate much faster, even in their early passage numbers, compared with NT-3 with a doubling time of more than 240 hours under growth factorstimulated conditions.…”

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

“…Moreover, the immunosuppressor leflunomide and its metabolite teriflunomide have been demonstrated to be able to inhibit BON-1 cells proliferation and to induce G2/M phase arrest [ 26 ]. Lithium treatment caused a dose-dependent reduction in BON-1 growth [ 28 ] as well as sodium butyrate and hexamethylene bisacetamide [ 30 ] and all-trans-retinoic acid [ 25 ]. These cells are known to exhibit constitutively activated phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling.…”

The Role of Cell Lines in the Study of Neuroendocrine Tumors

“…5-HT and IGF-1 stimulate the growth of BON1 cells and act as an autocrine growth factor through specific receptors [50,51]; endogenously released IGF-1 also regulates CgA secretion [52]. The growth of BON1 cells is inhibited strongly by sodium butyrate and hexamethylene bisacetamide [53], as well as by all- trans -retinoic acid [54]. BON1 cells express functional CRF receptor 2 which is linked to the release of serotonin, suggesting that the cells may be a target for CRF and/or human urocortin 3 in the intestine during stress-related responses [55].…”