Evaluation of Role of Telmisartan in Combination with 5-Fluorouracil on Gastric Cancer Cachexia

Abstract

Cancer cachexia is a multifactorial syndrome which comprises of loss of skeletal muscle and adipose tissue and may be accompanied with anorexia and an dysregulated metabolic state with increased basal energy expenditure. Cachexia worsens the survival of cancer patients and interferes with the quality of life of patients. Patients with cachexia are less tolerant to chemotherapeutic treatment and those patients who undergo surgery develop postoperative complications, hence cachexia contributes significantly to an increase in morbidity and mortality with poor quality of life in cancer patients Peroxisome proliferator-activated receptor γ (PPAR-γ) can inhibit proliferation of several cancer cells. Furthermore, PPARγ ligands have been shown to be potent inhibitors of angiogenesis, and a master regulator of adipogenesis. Angiotensin II directly induces muscle protein catabolism through the proteosome proteolytic pathway. Thus, targeting PPAR γ and angiotensin II appears to be an important strategy in control of cachexia and cardiovascular complications associated with cancer. Telmisartan is an AT1 receptor blocker and a partial agonist of PPAR-γ. Studies have reported that telmisartan promotes adipogenesis, inhibits angiogenesis and has an anti-inflammatory property by acting on PPAR-γ and angiotensin-II and hence can be a promising drug in treating cachexia. In light of this, the objective of present study was to evaluate the role of telmisartan in combination with 5-flourouracil (5-FU) in cachexia associated with gastric cancer. Adult male wistar rats of 6-8 weeks and weighing 250-500gms were taken. Upper Gastrointestinal cancer was induced by administering N-methyl-N′-nitro-Nnitrosoguanidine (MNNG) 200 mg/kg body weight once daily by oral gavage for two weeks, and saturated NaCl (1 ml per rat) was then given once every 3 days for 4 weeks. 5-Flourouracil (75mg/kg,i.v. was administered once three weeks from 7th week. Telmisartan(5mg/kg, p.o) was also administered along with 5-FU from 7th week. At the end of 22 weeks, various biochemical parameters, hemodynamic parameters, cachexia markers, tumor markers and oxidative stress parameters were measured and histopathological studies of stomach and tibilias anterior skeletal muscle was carried out. Gastric cancer control rats showed significantly decreased food intake and body weight.Chronic treatment with combination of telmisartan with 5-FU produced significant increase in food intake and body weight while chronic treatment with 5-FU alone did not produce any change in food intake and body weight. MNNG produced an significant decrease in the carcass weight and dry weight of Extensor digitorum longus (EDL) muscle. Chronic treatment of telmisartan in combination with 5-FU produced a significant increase in carcass weight and dry weight of EDL while treatment with 5-FU alone produced increase in dry weight of EDL without any change in carcass weight. In addition to this, there was a significant increase in cachexia markers like serum glucose, insulin, C-Reactive Protein (CRP) and Interleukin-6 (IL-6) in MNNG treated cancer control rats. Chronic treatment of telmisartan in combination with 5-FU significantly reduced serum glucose, insulin, CRP and IL-6 while treatment with 5-FU alone did not produce any change in serum glucose, insulin, CRP and IL-6. MNNG produced a significant decrease in total cholesterol, HDL, triglycerides and VLDL levels. Chronic treatment of telmisartan in combination with 5-FU significantly reduced in total cholesterol, HDL, triglycerides and VLDL levels while chronic treatment with 5-FU alone did not produce any change in total cholesterol, HDL, triglycerides and VLDL levels. MNNG produced a significant increase in tumor markers like Lactate dehydrogenase (LDH) and Gamma glutamyl transferase (GGT). In the group treated with combination of telmisartan with 5-FU there was no significant change in the LDH levels, however chronic treatment with 5-FU alone produced significant reduction in the LDH levels. Further, there was a significant decrease in GGT levels in the group treated with combination of 5-FU and telmisartan while chronic treatment with 5-FU alone did not produce any change in GGT levels. MNNG treated rats exhibited a significant increase in the blood pressure and a significant decrease in the heart rate, rate of pressure development and decay.Chronic treatment of telmisartan in combination with 5-FU significantly decreased the blood pressure and heart rate and significantly increased the rate of pressure development and decay while chronic treatment with 5-FU alone did not produce any change in hemodyanamic parameters. MNNG treated control rats exhibited a significant increase in Malondialdehyde (MDA) and significant decrease in Glutathione (GSH) and Superoxide dismutase (SOD) levels in the stomach tissue. Chronic treatment of telmisartan in combination with 5-FU significantly decreased MDA levels and significantly increased GSH and SOD levels while chronic treatment with 5-FU alone produced a significant increase in GSH levels whereas there was no significant change in SOD levels. Histopathological studies of forestomach revealed that MNNG induced well-differentiated squamous cell carcinomas. These tumors displayed increased cell proliferation, coupled with apoptosis, hyperkeratosis, keratohyaline granules and invasive carcinoma. The histopathological studies of forestomach from rats treated with 5-FU alone and combination of telmisartan with 5- FU depicted significant decrease in the cell proliferation, apoptosis, hyperkeratosis, keratohyaline granules and invasive carcinoma. The histopathological studies of tibilias anterior skeletal muscle revealed that there was marked muscle atrophy in cancer control rats which was characterized by decreased interstitial space and diminished nuclei. Chronic treatment of 5-FU and combination of telmisartan with 5- FU produced a control in muscle atrophy which was characterized by an increase in interstitial space and the number of nuclei In conclusion, our data suggests that combination of telmisartan with 5-FU treatment is beneficial in controlling cancer cachexia as depicted by prevention of skeletal muscle wasting and control in cachexia markers like glucose, insulin, CRP and IL-6. Telmisartan also prevents cardiovascular dysfunctioning associated with gastric cancer. Thus telmisartan can be used as an add-on therapy with 5-FU or other traditional chemotherapeutic agents for treatment of gastric cancer to control cachexia, thereby improving the quality of life of cancer patients.