Evaluation of Liver X Receptor (LXR) Agonist in Lung Cancer Induced-Cachexia

Abstract

EVALUATION OF LIVER X RECEPTOR (LXR) AGONIST IN LUNG CANCER INDUCED- CACHEXIA BACKGROUND AND OBJECTIVE: Cancer cachexia is defined as multifactorial syndrome due to loss of muscle mass with or without loss of fat which leads to progressive functional impairment that cannot be reversed by conventional nutritional intake. Weight loss with greater than 5% of body weight in last 6 months of period is established criteria for diagnosing cancer cachexia. Cancer cachexia is a wasting disorder with characterized by specific skeletal muscle and adipose tissue loss. Cancer cachexia is also driven by inflammation, altered metabolic changes such as increased energy expenditure, elevated plasma glucose, insulin resistance and excess catabolism. In cachexia, host-tumor interaction causes release of lactate and other inflammatory cytokines. Lactate released by tumor cells take part in hepatic glucose production with the help of gluconeogenic enzymes. Thus, cori cycle between organs and cancerous cells contribute to increased glucose production and energy expenditure. High amount of blood glucose leads to increased production insulin. Overproduction of insulin causes inactivation of PI3K/Akt/m-TOR pathway and finally results in insulin resistance. At present, pharmaconutrients like omega-3 fatty acids, progestins, ghrelin agonist like anamorelin, corticosteroids, selective androgen receptor modulator (SARM), cannabinoids, NSAIDs and physical exercise are used as current strategies for improving cachexia in cancer patients. Although very limited study concerning the efficacy of these proposed interventions are currently available). Since, single therapy was unable to reverse the wasting related to cachexia, treatment involving combination therapy and novel targets are the need of the hour. Nuclear receptors like liver X receptors (LXRs) are known to regulate various physiological functions like cholesterol and carbohydrate metabolism, energy expenditure and inflammation. Cholesterol derivatives, oxysterols were the first endogenous ligand found to activate LXRs whereas T0901317 and GW3965 were the potential synthetic LXR agonist reported. Various report suggests that proton pump inhibitor, Lansoprazole found to activate LXRs and also beneficial in cardiovascular disease. Hence, we selected Lansoprazole to study its effect in cancer cachexia and in cardiovascular complications. The objective of study is to evaluate effect of LXR agonist on cancer cachexia and cardiovascular complications and to develop the treatment strategies for lung cancer induced cachexia. MATERIALS AND METHOD: The study was carried out using Urethane induced- lung cancer in male Balb/c mice of 6-8 weeks’ age weighing (20-25g) were taken for the study. Urethane (1gm/kg) dissolved in sterile saline given intraperitoneally into the Balb/c mice. Urethane was given eight times every three days upto 21 days and followed by latency period upto 60th day for tumor growth. Following this Cisplatin (6mg/kg) was given on 1st day and 21st day after induction of cancer. Treatment with Lansoprazole (8mg/kg/day) was given intraperitoneally for 30 days. Parameters such as tumor markers, body mass parameters, inflammatory markers, carbohydrate and lipid metabolism markers, skeletal muscle wasting and cardiac complications parameters were evaluated. RESULTS: Tumor markers: After 12 weeks, cancer cachexic mice (disease control group) displayed a significant increase in lung weight as compared to normal control group. Cisplatin (6mg/kg) as well as combination of cisplatin and lansoprazole (8mg/kg) produced significant decrease in lung weight and lung to body weight ratio when compared to disease control group. Body mass markers: After 12 weeks, cancer cachexic mice (disease control group) showed significant reduction in body weight, food and water intake, carcass weight and delta lean mass when compared to normal control group. Cisplatin did not produce any significant increase in body weight, food and water intake, carcass weight and rather worsened it, except for delta lean mass which was not worsened when compared to diseased control animals. Treatment with combination of cisplatin (6mg/kg) and lansoprazole (8mg/kg) in disease induced animals produced significant increase in body weight, food and water intake, carcass weight and lean mass as compared to diseased control animals and cisplatin treated animals. Inflammatory marker: After 12 weeks, cancer cachexic mice (disease control group) showed significant elevation in CRP level when compared to normal control group. Cisplatin in diseased induced animals did not showed significant decrease in CRP level rather worsened it when compared to diseased control animals. Treatment with combination of cisplatin (6mg/kg) and lansoprazole (8mg/kg) in disease induced animals produced significant reduction in CRP level compared to diseased control animals and cisplatin treated animals. Markers of carbohydrate metabolism: After 12 weeks, cancer cachexic mice (disease control group) showed significant elevation in glucose level when compared to normal control group. Cisplatin in diseased induced animals did not showed significant decrease in glucose level rather worsened it when compared to diseased control animals. Treatment with combination of cisplatin (6mg/kg) and lansoprazole (8mg/kg) in disease induced animals produced significant reduction in glucose level compared to diseased control animals and cisplatin treated animals. Marker of lipid metabolism: After 12 weeks, cancer cachexic mice (disease control group) showed significant reduction in adipose tissue fat and lipid profile when compared to normal control group. Cisplatin did not produce any significant increase in adipose tissue fat and lipid profile and rather worsened it when compared to diseased control animals. Treatment with combination of cisplatin (6mg/kg) and lansoprazole (8mg/kg) in disease induced animals produced significant increase in adipose tissue fat and lipid profile as compared to diseased control animals and cisplatin treated animals. Skeletal muscle wasting markers: After 12 weeks, cancer cachexic mice (disease control group) showed significant reduction in all muscle weights when compared to normal control group. Cisplatin did not produce any significant increase in all muscle weights and rather worsened it when compared to diseased control animals. Treatment with combination of cisplatin (6mg/kg) and lansoprazole (8mg/kg) in disease induced animals produced significant increase in muscle weights except quadriceps, EDL and gastrocnemius weights as compared to diseased control animals and cisplatin treated animals. Cardiac parameters: After 12 weeks, cancer cachexic mice (disease control group) showed significant reduction in cardiac atrophic index and increase in CK-MB and LDH when compared to normal control group. Cisplatin did not produce any significant increase in cardiac atrophic index and decrease in CK-MB and LDH and rather worsened it when compared to diseased control animals. Treatment with combination of cisplatin (6mg/kg) and lansoprazole (8mg/kg) in disease induced animals produced significant increase cardiac atrophic index and decrease in CK-MB and LDH as compared to diseased control animals and cisplatin treated animals. CONCLUSION: Our data suggest that lansoprazole, a liver X receptor (LXR) agonist showed beneficial effect in cancer cachexia also improved cardiovascular complications in lung cancer-induced cachexic mice. However, cisplatin produced worsening effect in carcass weight, muscle wasting, lipolysis, anorexia, altered carbohydrate metabolism and inflammation. Combination of cisplatin with lansoprazole showed beneficial effect and thus, lansoprazole along with other chemotherapy agents can be beneficial in overcoming cachexia in cancer patients.