Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US with the majority of deaths due to metastatic disease. Current chemotherapeutic regimens involve highly toxic agents, which limits their utility; therefore, more effective and less toxic agents are required to see a reduction in CRC mortality. Novel fluorinated N,N′-diarylureas (FND) were developed and characterized by our group as potent activators of adenosine monophosphate- activated kinase (AMPK) that inhibit cell cycle progression. The purpose of this study was to determine the effect of a lead FND compound, FND-4b, either alone or combined with PI-103 (a dual PI3K/mTOR inhibitor) or SN-38 (active metabolite of irinotecan) on cell cycle arrest and apoptosis of CRC cell lines (both commercially-available and novel lines established from our patient population). Treatment with FND-4b for 24h resulted in a marked induction of phosphorylated AMPK expression and a concomitant reduction in markers of cell proliferation, such as cyclin D1, in all CRC cell lines. Apoptosis was also notably increased in CRC cells treated with FND-4b. Regardless of the genetic profile of the CRC cells, FND-4b treatment alone resulted in decreased cell proliferation. Moreover, the combination of FND-4b with PI-103 resulted in increased cell death in all cell lines, while the combination of FND-4b with SN-38 resulted in increased cell death in select cell lines. Our findings identify FND-4b, which activates AMPK at micromolar concentrations, as a novel and effective inhibitor of CRC growth either alone or in combination with PI-103 and SN-38.
|State||Published - Oct 1 2019|
Bibliographical noteFunding Information:
National Cancer Institute (https://www. cancer.gov/): P30 CA177558 (B.M.E.), R01 CA195573 (B.M.E.); National Institutes of Health (https://www.nih.gov/): T32 CA160003 (B.M.E.), P20 GM121327 (Y.Y.Z.), R01 CA172379 (C.L.); Markey Cancer Foundation (https://ukmarkey.org/): NoID (B.M.E.). We would like to acknowledge and thank the Markey Cancer Center Biostatistics and Bioinformatics Shared Resource Facility (SRF) for statistical analyses, the Markey Cancer Center Biospecimen Procurement and Translational Pathology SRF for procuring the tumor specimens used to develop our PDX models, and the Markey Cancer Center Research Communications Office for help with manuscript submission. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the grant funding agencies.
© 2019 Sinner et al.
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