Preventive Effects of Pentoxifylline on the Development of Colonic Premalignant Lesions in Obese and Diabetic Mice

Abstract

Obesity and its related metabolic abnormalities, including enhanced oxidative stress and chronic inflammation, are closely related to colorectal tumorigenesis. Pentoxifylline (PTX), a methylxanthine derivative, has been reported to suppress the production of tumor necrosis factor (TNF)-α and possess anti-inflammatory properties. The present study investigated the effects of PTX on the development of carcinogen-induced colorectal premalignant lesions in obese and diabetic mice. Male C57BL/KsJ-db/db mice, which are severely obese and diabetic, were administered weekly subcutaneous injections of the colonic carcinogen azoxymethane (15 mg/kg body weight) for four weeks and then received drinking water containing 125 or 500 ppm PTX for eight weeks. At the time of sacrifice, PTX administration markedly suppressed the development of premalignant lesions in the colorectum. The levels of oxidative stress markers were significantly decreased in the PTX-treated group compared with those in the untreated control group. In PTX-administered mice, the mRNA expression levels of cyclooxygenase (COX)-2, interleukin (IL)-6, and TNF-α, and the number of proliferating cell nuclear antigen (PCNA)-positive cells in the colonic mucosa, were significantly reduced. These observations suggest that PTX attenuated chronic inflammation and oxidative stress, and prevented the development of colonic tumorigenesis in an obesity-related colon cancer model.

Suppressive effects of the sodium‑glucose cotransporter 2 inhibitor tofogliflozin on colorectal tumorigenesis in diabetic and obese mice

“…Previously, it was reported that diet-or drug-induced diabetic and obese mice were significantly susceptible to colon tumorigenesis in carcinogen-induced colon cancer models (12,13). In addition, recent studies have revealed that several types of natural compounds and medicines, including catechins obtained from green tea, curcumin, and pentoxifylline suppressed the development of diabetesand obesity-related colorectal tumorigenesis partially by attenuating chronic inflammation (14)(15)(16). These findings indicated that diabetes-and obesity-associated metabolic abnormalities may be important targets for preventing colon cancer development in diabetic and/or obese individuals (10).…”

Inhibitory effects of pentoxifylline on inflammation-related tumorigenesis in rat colon

“…Among the candidates for CRC chemoprevention, COX-2 inhibitors, 5-ASA, and certain types of phytochemicals, such as green tea catechins, which possess anti-inflammatory and anti-oxidant effects, have shown promising results [ 26 – 28 ]. In this study, we focused on evaluating the effectiveness of PTX against CRC development, because it is reported to have anti-cancer activities besides being anti-inflammatory [ 10 , 13 , 29 ]. Moreover, because this compound has already been used as a drug, the feasibility of its clinical application is already established [ 8 , 9 ].…”

“…These observations are important, because the increased level of COX-2 contributes to the development of CRC; therefore, targeting this molecule can be an effective strategy for chemoprevention of CRC [ 31 , 32 ]. Using several colorectal carcinogenesis models, various agents, including COX-2 inhibitors, have been reported to inhibit the expression of COX-2, leading to the suppression of CRC development [ 13 , 22 , 28 , 33 ]. In our study, PTX inhibited the expression of COX-2 in the colonic mucosa, which probably led to the suppression of colorectal carcinogenesis.…”

“…In addition, PTX has been reported to suppress the synthesis of tumor necrosis factor (TNF)-α and oxidative stress and to improve the pathophysiological conditions in chronic inflammatory diseases [ 11 , 12 ]. A recent paper reported that PTX has preventive effects on CRC development in a mouse model of azoxymethane (AOM)-induced and obesity-related colorectal carcinogenesis, primarily through the attenuation of inflammation and reduction of oxidative stress in the colonic mucosa [ 13 ].…”

Prevention of Colorectal Cancer by Targeting Obesity-Related Disorders and Inflammation

“…Branched-chain amino acid (BCAA) supplements, containing essential amino acids such as leucine, isoleucine, and valine could alleviate protein malnutrition and exert anti-cancer properties by ameliorating insulin resistance [ 22 ]. Pharmaceutical approaches using the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pitavastatin, anti-hypertensive drugs, histamine receptor antagonists, and an anti-inflammatory agent pentoxifylline have been investigated and reported to attenuate chronic inflammation and reduce oxidative stress, leading to the prevention of colonic neoplastic lesion development [ 17 , 20 , 23 , 24 , 25 , 26 , 27 , 28 ].…”