Azacyclic FTY720 Analogues That Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo

Chen, Bin; Roy, Saurabh G; McMonigle, Ryan J; Keebaugh, Andrew; McCracken, Alison N; Selwan, Elizabeth; Fransson, Rebecca; Fallegger, Daniel; Huwiler, Andrea; Kleinman, Michael T; Edinger, Aimee L; Hanessian, Stephen (2016). Azacyclic FTY720 Analogues That Limit Nutrient Transporter Expression but Lack S1P Receptor Activity and Negative Chronotropic Effects Offer a Novel and Effective Strategy to Kill Cancer Cells in Vivo. ACS Chemical Biology, 11(2), pp. 409-414. American Chemical Society 10.1021/acschembio.5b00761

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FTY720 sequesters lymphocytes in secondary lymphoid organs through effects on sphingosine-1-phosphate (S1P) receptors. However, at higher doses than are required for immunosuppression, FTY720 also functions as an anticancer agent in multiple animal models. Our published work indicates that the anticancer effects of FTY720 do not depend on actions at S1P receptors but instead stem from FTY720s ability to restrict access to extracellular nutrients by down-regulating nutrient transporter proteins. This result was significant because S1P receptor activation is responsible for FTY720s dose-limiting toxicity, bradycardia, that prevents its use in cancer patients. Here, we describe diastereomeric and enantiomeric 3- and 4-C-aryl 2-hydroxymethyl pyrrolidines that are more active than the previously known analogues. Of importance is that these compounds fail to activate S1P1 or S1P3 receptors in vivo but retain inhibitory effects on nutrient transporter proteins and anticancer activity in solid tumor xenograft models. Our studies reaffirm that the anticancer activity of FTY720 does not depend upon S1P receptor activation and uphold the promise of using S1P receptor-inactive azacyclic FTY720 analogues in human cancer patients.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Fallegger, Daniel and Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1554-8929

Publisher:

American Chemical Society

Language:

English

Submitter:

Debora Scherrer

Date Deposited:

22 Feb 2016 17:09

Last Modified:

22 Feb 2016 17:09

Publisher DOI:

10.1021/acschembio.5b00761

PubMed ID:

26653336

BORIS DOI:

10.7892/boris.76760

URI:

https://boris.unibe.ch/id/eprint/76760

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