Evaluation of Role of Telmisartan on Oral Cancer Cachexia

Abstract

Background and Objective: Cancer cachexia is a multi-factorial syndrome that encompasses the effects of the tumor on the host other than those resulting from mechanical interference with vital organs and this reduces response to anti-tumor therapies and contributes to increased mortality. Cachexia occurs very frequently in patients with lung and upper gastrointestinal cancer and the best way to cure cachexia is to cure the cancer and a clear focus on optimal oncological management is important. PPAR-γ ligands have shown to inhibit tumor growth and progression in preclinical models of cancer and can be used for the decreasing the energy expenditure in the patients suffering from the cachexia and increasing the differentiation of adipocytes and causing an increase in weight of the cancer patients. Telmisartan is a partial agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ). In light of these, the objectives of the present study were; 1. To evaluate the role of telmisartan in oral cancer cachexia using chemically induced model of oral cancer. 2. To develop therapeutic strategy for oral cancer cachexia. Material and Methods: Wistar rats of 200-300g were taken and 0.5% 4-NQOin propylene glycol was applied to tongue by size no. 4 paint brush, thrice a week for 8 weeks. Cisplatin (0.23mg/kg) was administered intravenously once in three weeks from 8- 22 weeks and telmisartan (5 mg/kg/day, p.o) was administered daily from 8-22 weeks. At the end of 22 weeks, various biochemical parameters, hemodynamic parameters, cachexia markers, tumor markers, oxidative stress parameter were measured and histopathological studies of tongue was carried out. Results: Oral cancer control rats showed decreased food intake and body weight. Treatment with combination of telmisartan with cisplatin produced significant increase in food intake and body weight while cisplatin alone did not produce any increase in food intake and body weight. 4-NQO produced significant hyperglycemia and dyslipidemia which includes increased serum glucose and decreased total cholesterol, triglycerides, VLDL, HDL. Treatment with combination of telmisartan with cisplatin produced significant decrease in serum glucose and significant increase in serum lipid profile while cisplatin alone did not produced any increase in serum lipid profile. 4-NQO produced hemodenamic changes accompanying hypertension, increased heart rate, reduced rate of pressure development and decay, treatment with combination of telmisartan with cisplatin produced significant decrease in blood pressure and significant increase in heart rate and rate of pressure development and deacay while cisplatin alone did not improve hemodynamic parameters. 4-NQO produced significant increased levels of cachexia markers viz insulin, CRP, IL-6, which was reduced significantly on treatment with combination of telmisartan with cisplatin and not with alone cisplatin. 4-NQO increased levels of tumor markers viz LDH, GGT which was reduced significantly on treatment with combination of telmisartan with cisplatin and not with alone cisplatin. 4-NQO significantly decreased antioxidant level (SOD, GSH) and significantly increased prooxidant (MDA) levels which were reversed on treatment with combination of telmisartan with cisplatin. Treatment with cisplatin alone significantly reduced MDA levels; however did not produce increase in anti-oxidants SOD & GSH levels. 4-NQO produces histopathological changes in tongue mucosa from normal epithelium, hyperplasia and hyperkeratosis, pre-malignant dysplasia, and carcinoma in situ to invasive squamous cell carcinoma which was improved on treatment with cisplatin; however, treatment with combination of telmisartan with cisplatin depicted better improvement. Conclusions: Our data suggests that combination of telmisartan with cisplatin treatment is beneficial in controlling cancer cachexia as depicted by decreased levels of cachexia markers, prevention of hyperglycemia, hyperinsulinemia, dyslipidemia, hypertension, further the combination treatment improved the tumor markers like LDH, GGT, antioxidant like SOD & GSH and prooxidant (MDA). Thus telmisartan can be used as an addon therapy with cisplatin or other traditional chemotherapeutic agents for treatment of oral cancer and control cachexia, thereby increasing the quality of life of cancer patients.