Efficacy of telotristat ethyl: A peripheral tryptophan hydroxylase inhibitor that blocks serotonin biosynthesis against cultured liposarcoma, colon cancer, and cholangiocarcinoma cell lines.

Abstract

e15602 Background: Serotonin (5-HT) is most often considered a neurotransmitter—but in reality its main function is to promote cell proliferation at the site of wound healing via platelet degranulation. We tested the hypothesis that blocking 5-HT production in cancer cells might lead to their death by exposure to a specific tryptophan hydroxylase (TPH) inhibitor: telotristat ethyl (TE). The advantage of this TPH inhibitor is that it does not cross the blood brain barrier and therefore can be used to treat peripheral cancers without danger of interfering with central nervous system 5-HT production. Methods: Three cancer cell lines were tested: liposarcoma (94T778), colon cancer (HT-29), and cholangiocarcinoma (TFK-1). The cells were grown with 0, 5, 15 and 30 µM TE, plated into four-chambered slides with an initial confluence of at least 30%, and cultured for 24-96 H. At the end of each 24 hour period slides were removed, washed, fixed, and stained with hematoxylin for density assessment. Experiments were performed in triplicate and repeated in at least three separate experiments. Cell confluence was determined under low power microscopic examination. Results: In the absence of TE the three cell lines increased their confluence from approximately 30% to 83±5.8% (94T778), 68±11% (HT-29), and 60±16% (TFK-1) over 96 H. When the 94T778 cells were exposed to increasing concentrations of TE their confluence decreased progressively. At a dose of 30 µM cell confluence at 24 H was 3±0%, at 48 H 0.3±0.6%, at 72 H 0±0%, and at 96 H 0±0%. For the HT-29 cells, cell confluence in the 30 µM TE groups were 12±8%, 3±3%, 7±5% and 2±1% at 24, 48, 72 and 96 H, respectively. For the TFK-1cells, cell confluence in the 30 µM TE groups were 7±3%, 20±14%, 17±14% and 24±16% at 24, 48, 72 and 96 H, respectively. Conclusions: Telotristat ethyl is a potent inhibitor of tumor cell line growth. However, the efficacy of this inhibition varies between cell lines. The liposarcoma cell line was most sensitive to TE, with the cholangiocarcinoma cell line being moderately impacted. The colon cancer cell line was intermediate between these two. The differences in response to TE may be related to the specific expression of TPH in any particular cell line, with cancers that are more dependent on 5-HT production being most impacted by TPH blockade. Just as ER PR positive breast cancers are sensitive to blockade of these receptors, TPH positive cancers may be successfully targeted by specific inhibition of the 5-HT biosynthetic pathway.