Nonsteroidal anti-inflammatory drugs (NSAIDs) strongly inhibit tumorigenesis in experimental animal models, but toxicity from cyclooxygenase (COX) inhibition limits their use in humans for cancer chemoprevention. Previous studies have concluded that a COX-independent mechanism is responsible their antineoplastic activities, which suggests that it may be feasible to develop safer and more efficacious drugs by targeting such mechanisms. We have found that the tumor cell growth inhibitory and apoptosis inducing properties of certain NSAIDs such as sulindac sulfide (SS) are closely associated with inhibition of the cGMP-specific phosphodiesterase, PDE5. SS can selectively inhibit PDE5 to increase intracellular cGMP levels and activate protein kinase G to phosphorylate 2-catenin, thereby inducing its degradation to suppress the transcription of key apoptosis regulatory proteins such as survivin. Recently, we have shown that siRNA knockdown of PDE5 can selectively induce apoptosis of tumor cells as does SS. The proposed studies will focus on breast cancer chemoprevention since PDE5 appears to be the predominant cGMP degrading isozyme in breast tumor cells that is also expressed in adenocarcinomas from breast cancer patients. We hypothesize that PDE5 plays an important role in breast tumorigenesis that can be targeted to develop safe and efficacious drugs for breast cancer chemoprevention. In support of this hypothesis, we have synthesized a series of novel tadalafil derivatives that potently and selectively inhibit the growth and induce apoptosis of breast tumor cells. To further test this hypothesis, Aim 1 will determine the importance of PDE5 and cGMP signaling for the anticancer activity of novel tadalafil derivatives and will evaluate PDE5 expression in human breast tumors;
Aim 2 will synthesize and evaluate novel tadalafil derivatives for in vitro anticancer activity and will identify candidates with optimal pharmacological properties for in vivo efficacy testing;
and Aim 3 will evaluate chemopreventive efficacy and safety of an optimal tadalafil derivative and will confirm mechanism of action in vivo. The goals of these studies are to validate PDE5 as an anticancer target, determine its potential role in cancer, and identify a safe and effective tadalafil derivative for preclinical drug development.
The public health impact of breast cancer is substantial with nearly one-fourth of the 180,000 cases diagnosed each year in the US resulting in death and greater than a 40% death rate worldwide. Besides the human toll of the disease, the economic strain to manage the diagnosis and treatment of this most common form of cancer in women is enormous. An important classification of breast tumors is based on the presence or absence of the estrogen receptor (ER). While the majority of breast cancers are ER+, approximately 30% are ERnegative. Patients with ER- disease are not sensitive to estrogen receptor antagonists or aromatase inhibitors that are commonly used for the management of ER+ disease and have a poorer clinical outcome compared to women with ER+ disease. As such, there is an urgent medical need for chemopreventive drugs to manage ER- breast cancer. We propose studies to develop a novel molecular target and class of compounds for chemoprevention of ER- breast cancer and which may also have potential for therapy.
|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 TGFÎ²/miR-21 signaling. Oncotarget 7:7979-92|
|Lee, Kevin; Lindsey, Ashley S; Li, Nan et al. (2016) Î²-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget 7:5353-65|
|Li, Nan; Chen, Xi; Zhu, Bing et al. (2015) Suppression of Î²-catenin/TCF transcriptional activity and colon tumor cell growth by dual inhibition of PDE5 and 10. Oncotarget 6:27403-15|
|Koneczny, Inga; Schulenburg, Axel; Hudec, Xenia et al. (2015) Autocrine fibroblast growth factor 18 signaling mediates Wnt-dependent stimulation of CD44-positive human colorectal adenoma cells. Mol Carcinog 54:789-99|
|Li, N; Lee, K; Xi, Y et al. (2015) Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and Î²-catenin-dependent TCF transcriptional activity. Oncogene 34:1499-509|
|Zhang, Huang-Ge; Grizzle, William E (2014) Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol 184:28-41|
|Gurpinar, Evrim; Grizzle, William E; Piazza, Gary A (2014) NSAIDs inhibit tumorigenesis, but how? Clin Cancer Res 20:1104-13|
|Aboul-Fadl, Tarek; Al-Hamad, Suliman S; Lee, Kevin et al. (2014) Novel non-cyclooxygenase inhibitory derivatives of naproxen for colorectal cancer chemoprevention. Med Chem Res 23:4177-4188|
|Tinsley, Heather N; Grizzle, William E; Abadi, Ashraf et al. (2013) New NSAID targets and derivatives for colorectal cancer chemoprevention. Recent Results Cancer Res 191:105-20|
|Gurpinar, Evrim; Grizzle, William E; Shacka, John J et al. (2013) A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy. Mol Cancer Ther 12:663-74|
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