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© The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. 1,4-Dihydroxy-2-naphthoic acid (1,4-DHNA) is a bacterial-derivedmetabolite that binds the aryl hydrocarbon receptor (AhR) and exhibits anti-inflammatory activity in the gut. The structure-dependent AhR activity of hydroxyl/carboxy-substituted naphthoic acids (NAs)was determined in young adultmouse colonic (YAMC) cells and human Caco2 colon cancer cells using CYP1A1/CYP1B1mRNAs asAh-responsive genes. Compounds used in this study include 1,4-, 3,5-, and 3,7-DHNA, 1,4- dimethoxy-2-naphthoic acid (1,4-DMNA), 1- and 4-hydroxy-2-naphthoic acid (1-HNA, 4-HNA), 1- and 2-naphthoic acid (1-NA, 2- NA), and 1- and 2-naphthol (1-NOH, 2-NOH). 1,4-DHNAwas themost potent compoundamong hydroxyl/carboxy naphthalene derivatives, and the fold induction response for CYP1A1 and CYP1B1was similar to that observed for 2,3,7,8-tetrachlorodibenzop- dioxin (TCDD) in YAMC and Caco2 cells. 1- and 4-HNAwere less potent than 1,4-DHNA but inducedmaximal (TCDD-like) response for CYP1B1 (both cell lines) and CYP1A1 (Caco2 cells).With the exception of 1- and 2-NA, all compounds significantly induced Cyp1b1 inYAMCcells and these responseswere not observed in AhR-deficient YAMC cells generated using CRISPR/ Cas9 technology. In addition,we also observed that 1- and 2-NOH(and 1,4-DHNA)wereweakAhR agonists, and 1- and 2-NOH also exhibited partialAhR antagonist activity. Structure-activity relationship studies for CYP1A1 but not CYP1B1were similar in both cell lines, and CYP1A1 induction required one or both 1,4-dihydroxy substituents and activitywas significantly enhanced by the 2-carboxyl group.We also used computational analysis to showthat 1,4-DHNAand TCDDshare similar interactions within the AhR binding pocket and differ primarily due to the negatively charged group of 1,4-DHNA.

Indira Jutooru,1 Gayathri Chadalapaka,1 Stephen Safe1,21Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA; 2Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USAAbstract: Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related deaths in developed countries and, in 2013, it is estimated that in excess of 45,220 new cases were diagnosed in the United States. PDAC is a highly aggressive disease that invariably evades early diagnosis. The mean survival time for patients with metastatic disease is only 3–6 months, and only 20%–30% of pancreatic cancer patients are alive after 12 months. Because pancreatic cancers are frequently detected at an advanced stage, treatments have provided very limited improvements in tumor regression and overall survival times after diagnosis. 5-Fluorouracil alone or in combination with other drugs has been extensively used for treatment of advanced pancreatic cancer, and gemcitabine has partially replaced 5-fluorouracil as a treatment for pancreatic cancer. Gemcitabine provides increased clinical benefits in terms of response rate; however, future studies need to focus on developing treatment modalities that will improve the survival rate for pancreatic cancer patients. Specificity protein 1 (Sp1) is overexpressed in PDAC patients, and high expression is associated with poor prognosis, lymph node metastasis, and low survival. Knockdown studies have shown that Sp1 plays an important role in cell growth, angiogenesis, inflammation, survival, and metastasis. Sp1 expression is low in normal tissue when compared to tumor tissue, which makes Sp1 a potential target for development of new mechanism-based drugs for treatment of pancreatic cancer. Several drugs such as tolfenamic acid, betulinic acid, and methyl-2-cyano3,12-dioxooleana-1,9(11)-dien-28-oate are shown to downregulate Sp1 expression through various pathways. This review summarizes the role of Sp1 in pancreatic cancer and delineates the mechanisms of action of various drugs that downregulate expression of Sp1 and other Sp transcription factors.Keywords: Sp transcription factors, microRNAs, ZBTB repressors, ROS