4.6 Article

The discovery of indolone GW5074 during a comprehensive search for non-polyamine-based polyamine transport inhibitors

Journal

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2021.106038

Keywords

Polyamines; Difluoromethylornithine; DFMO; Pancreatic cancer; Polyamine transport inhibitor; GW5074

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Polyamines play a critical role in cancer cell growth, and inhibiting their synthesis is important for anticancer strategies. The novel non-polyamine-based polyamine transport inhibitor GW5074 has been identified, which effectively inhibits the growth of human pancreatic cancer cells and reduces tumor growth in a murine pancreatic cancer model. The combination of GW5074 with DFMO shows potential to enhance anticancer activity in pancreatic cancers.
The native polyamines putrescine, spermidine, and spermine are essential for cell development and proliferation. Polyamine levels are often increased in cancer tissues and polyamine depletion is a validated anticancer strategy. Cancer cell growth can be inhibited by the polyamine biosynthesis inhibitor difluoromethylornithine (DFMO), which inhibits ornithine decarboxylase (ODC), the rate-limiting enzyme in the polyamine biosynthesis pathway. Unfortunately, cells treated with DFMO often replenish their polyamine pools by importing polyamines from their environment. Several polyamine-based molecules have been developed to work as polyamine transport inhibitors (PTIs) and have been successfully used in combination with DFMO in several cancer models. Here, we present the first comprehensive search for potential non-polyamine based PTIs that work in human pancreatic cancer cells in vitro. After identifying and testing five different categories of compounds, we have identified the cRAF inhibitor, GW5074, as a novel non-polyamine based PTI. GW5074 inhibited the uptake of all three native polyamines and a fluorescent-polyamine probe into human pancreatic cancer cells. GW5074 significantly reduced pancreatic cancer cell growth in vitro when treated in combination with DFMO and a rescuing dose of spermidine. Moreover, GW5074 alone reduced tumor growth when tested in a murine pancreatic cancer mouse model in vivo. In summary, GW5074 is a novel non-polyamine-based PTI that potentiates the anticancer activity of DFMO in pancreatic cancers.

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