NSAIDs significantly reduce the incidence and risk of death from colorectal cancer, but their long-term use for chemoprevention is not recommended because of potentially fatal side-effects resulting from cyclooxygenase (COX) inhibition and the suppression of physiological prostaglandins. Some investigators have concluded that the mechanism for the anticancer activity of NSAIDs may not require COX inhibition, but involves selective apoptosis induction of neoplastic cells and suggest that safer and more efficacious non-COX inhibitory derivatives can be developed by targeting the underlying pathway leading to apoptosis. We have extensively studied the mechanism by which the NSAID sulindac induces apoptosis and reported that this activity is closely associated with its ability to inhibit cyclic guanosine monophosphate phosphodiesterase (cGMP PDE), which activates cGMP/protein kinase G signaling to suppress oncogenic -catenin/Tcf-mediated transcriptional activity and the synthesis of key cell cycle regulatory proteins, such as cyclin D1 and survivin. We recently discovered that PDE10 is a critically important target of sulindac, which is elevated in colon tumors and essential for tumor cell growth. Using the indene scaffold of sulindac, we synthesized a series of non-COX inhibitory derivatives that selectively inhibit PDE10 and tumor cell growth. A prototype inhibitor, MCI-020 was identified with strong antitumor activity and the potential to inhibit metastasis. Further chemical optimization of MCI-020 and studies to better define the role of PDE10 in colorectal tumorigenesis are, however, necessary to develop this approach for chemoprevention. The following aims are proposed: 1) design and synthesize novel sulindac derivatives with selectivity to inhibit PDE10, 2) evaluate PDE10 selectivity and in vitro anticancer activity of sulindac derivatives, 3) determine in vivo anticancer activity of promising sulindac derivatives in mouse models of colon tumor growth and metastasis, and 4) measure PDE10 expression during colon tumorigenesis in whole animals and human clinical samples. The goal is to identify a lead compound with safety and efficacy attributes that will merit consideration for clinical trials. Elucidation of the role of PDE10 in colorectal tumorigeness may also provide insight to biomarkers and imaging methods for the early detection of cancer using radiopharmaceuticals.
The nonsteroidal anti-inflammatory drug, sulindac strongly inhibits adenoma formation in patients with familial adenomatous polyposis, but its long-term use for preventing colorectal cancer is limited by potentially fatal side-effects resulting from cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. We propose studies to chemically modify sulindac to block COX binding, while increasing potency and selectivity to inhibit PDE10, a novel cancer target we recently discovered to be overexpressed in colon tumor cells and essential for their growth. These studies are highly significant to human health because of their potential to identify a new drug candidate for the treatment of individuals at high risk of developing colorectal cancer as well as a biomarker for the early detection of colorectal cancer.
|Mathew, Bini; Hobrath, Judith V; Connelly, Michele C et al. (2018) Oxazole and thiazole analogs of sulindac for cancer prevention. Future Med Chem 10:743-753|
|Mathew, Bini; Snowden, Timothy S; Connelly, Michele C et al. (2018) A small diversity library of ?-methyl amide analogs of sulindac for probing anticancer structure-activity relationships. Bioorg Med Chem Lett 28:2136-2142|
|Keeton, Adam B; Salter, E Alan; Piazza, Gary A (2017) The RAS-Effector Interaction as a Drug Target. Cancer Res 77:221-226|
|Mathew, Bini; Hobrath, Judith V; Lu, Wenyan et al. (2017) Synthesis and preliminary assessment of the anticancer and Wnt/?-catenin inhibitory activity of small amide libraries of fenamates and profens. Med Chem Res 26:3038-3045|
|Mathew, Bini; Hobrath, Judith V; Connelly, Michele C et al. (2017) Diverse amide analogs of sulindac for cancer treatment and prevention. Bioorg Med Chem Lett 27:4614-4621|
|Zhu, Bing; Lindsey, Ashley; Li, Nan et al. (2017) Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking ?-catenin and MAPK signaling. Oncotarget 8:69264-69280|
|Piazza, Gary A (2017) Validation of PDE5 as a Chemoprevention Target. Cancer Prev Res (Phila) 10:373-376|
|Yi, Bin; Chang, Hong; Ma, Ruixia et al. (2016) Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGF?/miR-21 signaling. Oncotarget 7:7979-92|
|Lee, Kevin; Lindsey, Ashley S; Li, Nan et al. (2016) ?-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget 7:5353-65|
|Prasain, Jeevan K; Rajbhandari, Rajani; Keeton, Adam B et al. (2016) Metabolism and growth inhibitory activity of cranberry derived flavonoids in bladder cancer cells. Food Funct 7:4012-4019|
Showing the most recent 10 out of 44 publications