Multitargeted Low-Dose GLAD Combination Chemoprevention: A Novel and Promising Approach to Combat Colon Carcinogenesis

Abstract

Preclinical studies have shown that gefitinib, licofelone, atorvastatin, and α-difluoromethylornithine (GLAD) are promising colon cancer chemopreventive agents. Because low-dose combination regimens can offer potential additive or synergistic effects without toxicity, GLAD combination was tested for toxicity and chemopreventive efficacy for suppression of intestinal tumorigenesis in adenomatous polyposis coli (APC)(Min/+) mice. Six-week-old wild-type and APC(Min/+) mice were fed modified American Institute of Nutrition 76A diets with or without GLAD (25 + 50 + 50 + 500 ppm) for 14 weeks. Dietary GLAD caused no signs of toxicity based on organ pathology and liver enzyme profiles. GLAD feeding strongly inhibited (80-83%, P < .0001) total intestinal tumor multiplicity and size in APC(Min/+) mice (means ± SEM tumors for control vs GLAD were 67.1 ± 5.4 vs. 11.3 ± 1.1 in males and 72.3 ± 8.9 vs 14.5 ± 2.8 in females). Mice fed GLAD had >95% fewer polyps with sizes of >2 mm compared with control mice and showed 75% and 85% inhibition of colonic tumors in males and females, respectively. Molecular analyses of polyps suggested that GLAD exerts efficacy by inhibiting cell proliferation, inducing apoptosis, decreasing β-catenin and caveolin-1 levels, increasing caspase-3 cleavage and p21, and modulating expression profile of inflammatory cytokines. These observations demonstrate that GLAD, a novel cocktail of chemopreventive agents at very low doses, suppresses intestinal tumorigenesis in APC(Min/+) mice with no toxicity. This novel strategy to prevent colorectal cancer is an important step in developing agents with high efficacy without unwanted side effects.

Targeting mTOR and p53 Signaling Inhibits Muscle Invasive Bladder Cancer In Vivo

“…Therefore, simultaneous inhibition of multiple tumor cell pathways may result in more effective inhibition (34). Overall, our study clearly demonstrates for the first time that the combination of mTOR and p53 modulators has better inhibitory effects on urothelial tumor growth and invasion than the individual treatments, and supports the use of a combinational approach for better efficacy and management of cancers (34, 49–50). Importantly simultaneous targeting of mTOR and p53 pathways could be novel choice of treatment option for patients with non-muscle-invasive bladder cancer in the post-operative prevention setting with high risk for disease recurrence and progression to MIBC.…”

Chemoprevention of Urothelial Cell Carcinoma Growth and Invasion by the Dual COX–LOX Inhibitor Licofelone in UPII-SV40T Transgenic Mice

“…A dose-dependent inhibition of PCNA expression with an increase in apoptosis also was observed in licofelone-treated lung tumors (16) as well as colon tumors (15, 37). Similarly, dose-dependent inhibition of COX-2 and 5-LOX was observed with licofelone treatment in lung tumors (16).…”

Statins and Colorectal Cancer – A Systematic Review

“…Six studies were performed in animals to evaluate the effect of statins on the incidence of CRC and its precursors [34][35][36][37][38][39][40]. In the study by Sun et al, atorvastatin significantly suppressed incidence (by up to 52 %, P = 0.01) and the number of identified adenocarcinomas (reduction by 58 %, P = 0.01) in rats [34].…”