Oral administration of caffeic acid ameliorates the effect of cisplatin on brush border membrane enzymes and antioxidant system in rat intestine

Abstract

Cisplatin (CP) is a widely used antineoplastic drug that exhibits gastrointestinal toxicity. We have previously shown that administration of a single dose of CP results in a decrease in the activities of several brush border membrane (BBM) enzymes, induces oxidative stress and alters the activities of several antioxidant enzymes in the small intestine of rats. In the present study we have investigated the effect of treatment with the dietary antioxidant caffeic acid (CA) on CP induced biochemical changes in the intestine. Administration of a single intraperitoneal dose of CP alone (6 mg/kg body weight) led to a decrease in the activities of the BBM enzymes, increase in lipid peroxidation, decrease in sulfhydryl groups and changes in the activities of catalase, superoxide dismutase, glutathione peroxidase, glucose 6-phosphate dehydrogenase, glutathione reductase, glutathione S-transferase and thioredoxin reductase. Administration of two doses of CA (each of 250 mg/kg body weight), at 15 and 120 min after treatment with CP, significantly attenuated the CP-induced changes in all these parameters but the administration of CA alone had no effect. These results suggest that CA is an effective agent in reducing the effects of CP on the intestine and could prove to be useful in alleviating the gastrointestinal toxicity of this drug.

Introduction

Cis-diamminedichloroplatinum(II), commonly known as cisplatin (CP), is an inorganic compound containing a central platinum(II) atom coordinated to two amine groups and two chloride ions in cis configuration. It is a highly effective antineoplastic drug for the treatment of a diverse spectrum of malignancies (Cohen and Lippard, 2001). However, the use of high dose of CP is difficult in practice because of the associated adverse reactions such as renal damage, gastrointestinal dysfunction, auditory toxicity, myelosuppression and peripheral nerve toxicity. The prevention of side effects of CP is, therefore, one of the major issues in cancer treatment using this drug. Various methods to prevent or reduce the side effects of cisplatin, such as the use of free radical scavengers and chemoprotective agents, have been tested but effective methods for clinical use have not yet been established (Ali and Al Moundhri, 2006).

Increased production of reactive oxygen species (ROS) and free radicals has been implicated in mediating CP-induced toxicity. These radicals can cause extensive tissue damage by reacting with macromolecules like membrane lipids, proteins and nucleic acids. Inhibitors of ROS accumulation can block CP-induced toxicity indicating that pathways involved in and/or activated by oxidative stress are critical to CP bioactivity (Sheikh-Hamad et al., 1997, Ajith et al., 2007). Much attention in this regard has been paid to the protective effects of natural antioxidants (AO) against drug-induced toxicities especially where free radical generation is involved (Ajith et al., 2007, Weijl et al., 1997, Cetin et al., 2006) because of their effectiveness and relative safety in humans. The therapy using AO can be started soon after, simultaneously with or before the start of chemotherapy using antineoplastic drugs. There is evidence that administration of AO enhances the anticancer effects of chemotherapy and also reduces the toxicity of CP without interfering with its antitumor activity (Conklin, 2004, Leonetti et al., 2003, Bokemeyer et al., 1996).

Caffeic acid (CA) is a simple phenolic acid and catechol that is a common constituent of human diet. It is especially abundant in is coffee brew and beer and is easily absorbed from the gastrointestinal tract after consumption of these beverages (Renouf et al., 2010, Scalbert et al., 2002). CA is endowed with strong AO activity both under in vitro and in vivo conditions (Nardini et al., 1995). Its action as an oxygen radical scavenger and chain breaking AO is well documented (Laranjinha et al., 1994). CA is a superior AO in comparison to other phenolic acids such as p-coumaric, chlorogenic and ferulic acids in inhibiting LDL oxidation and preventing cardiovascular diseases (Nardini et al., 1995, Sato et al., 2011). It has been shown to protect rats from oxidative damage to liver caused by administration of nickel (Pari and Prasad, 2009).

The gastrointestinal toxicity of CP (which includes nausea, vomiting and diarrhea) is a major problem for patients undergoing cancer chemotherapy with this drug. However, only limited work has been done towards amelioration of the side effects of this drug on the gastrointestinal system. Histological analysis of small intestine of CP treated rats has revealed that CP impairs the mucosal structure by causing acute epithelial necrosis and apoptosis (Ikuno et al., 1995, Vijayalakshmi et al., 2006). We have previously shown that administration of a single intraperitoneal dose of CP to rats results in lowered activities of enzymes in the brush border membrane (BBM) lining the epithelial cells of intestine. It also led to increased production of ROS and alterations in the activities of several AO enzymes (Arivarasu et al., 2007). The maximum changes were 3 days after the administration of the drug after which recovery took place. The objective of the present study was to examine the effect of oral administration of CA on CP-induced changes in the function of digestive enzymes and the AO system in rat intestine. This was done with a view to see if CA could be used to prevent or attenuate CP-induced gastrointestinal dysfunction.