Evaluation of Calcium Channel Blocker in Cardiac Complications Associated with Cancer Cachexia

Abstract

Background and objective Cancer cachexia is a syndrome which includes muti-factoial that 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. During cancer cachexia, heart functions are diminished in mice with tumor induced cachexia, and this impaired function is associated with increased fibrosis, disrupted myocardial structure and altered composition of contractile proteins of cardiac muscle. The cardioprotective agents like cilnidipine is the 4th generation calcium channel blocker which through its superior cardioprotective action and causes the cardiac dysfunction to eliminate. In the light to this the aim of the present study is: 1. To evaluate the role of cilnidipine in metastatic induced cancer cachexia. 2. To develop a therapeutic strategy for cancer cachexia. MATERIALS AND METHOD: Balb/c mice of either sex 6-8 weeks’ age weighing (20-25g) were taken for the study and were divided in 4 groups each containing 6 mice maintained under well- controlled conditions of temperature (22+-2 C), humidity (55+- 5%) and 12h light and dark cycle. Standard laboratory chow and UV filtered water was provided ad libitum. A rapid injection of large volume B16F1 cell suspension (2×106) into the mice tail vein was performed. The treatment was started from the zero days and was continued till 21st day in the control treated and disease treated group of animals. At the end of the study i.e. 21st day the blood was collected and the serum was separated. Cilnidipine was given as solution and was dissolved in distilled water in a dose of (3mg/kg). RESULTS: Cancer/ tumor markers: At the end of 21 days, cancer control mice exhibited a significant decrease in kidney weight whereas there was no significant change found to be exhibited in the lung, liver, spleen weights as compared to the control animals. A significant increase in the weight of the lung, liver, kidney, and spleen was seen in the animals treated with cilnidipine as compared to disease control animal. The control animals treated with cilnidipine did not produce any significant change in the lung, liver, kidney, spleen weight but produced a significant increase in the area. General cachexiac markers After the induction of B16F1 melanoma cell lines, a significant decrease in the body weight, food intake, water intake and activity in cancer control groups as compared to normal control groups. The animals treated with cilnidipine were found to show an increase in body weight, food intake, water intake, activity. Body mass marker A significant decrease was found in delta lean, carcass weight, EDL weight, soleus weight, gastronemius weight, peripheral weight in the cancer induced animals as compared to the normal control mice. Moreover, a significant increase was also observed in delta lean, carcass weight, EDL weight, soleus weight, gastronemius weight, peripheral weight, in the animals treated with cilnidipine as compared to the diseased animals. Hypertropic parameter: A significant increase in the cardic hypertropic index, hw/bw, collagen level decrease in lv hypertropic index, lv/rv weight in cancer induced mice compared to the control mice. There was a significant decrease in cardiac hypertropic index, HW/BW, collagen and a increase in LV hypertropic index, LV/RV weight. Hemodynamic parameters: B16-F1 induced mice exhibited significant increase in blood pressure and significant decrease in heart rate, rate of pressure development and decay as compared to control rats. Treatment with Cilnidipine (0.23mg/kg) alone did not show any significant change in blood pressure, heart rate and rate of pressure development and decay in cancer treated rats as compared to cancer control rats. Cardiac biomarker: There was a significant increase in the level of Troponin-I, C K-MB, LDH, CRP and a decrease in Na+K+ATPase in cancer mice as compared to the normal mice. However, a significant increase in the level of Troponin-I, CK-MB, LDH, CRP and a decrease in the Na+K+ATPase was seen in disease treated animals as compared to the diseased animals. Serum lipid profile: Cancer control mice were found to exhibit a significant decrease in the serum total cholesterol, triglyceride HDL and VLDL, LDL and log TG/HDL levels as compared to the normal control mice. Treatment with cilnidipine produces significant increase in serum total cholesterol, TG, HDL, VLDL, LDL and log TG/HDL levels in the cancer treated nice as compared to the cancer control mice. Histopathological analysis: The histopathological analysis of the longitudinal section of the left ventricule was done. The disease control animals exhibited decrease in the extracellular space and increased focal clustering. The animals treated with cilnidipine showed significant elevation in the extracellular space and decrease in the focal clustering. Oxidative stress parameters: A significant increase was found to be exhibited in the MDA levels in the disease control mice as compared to the disease control. Also a significant decrease in the SOD and GSH levels was seen in the animals in disease control mice as compared to normal control animals. A significant decrease in the MDA level and increase in SOD, GSH, total protein in disease treated with cilnidipine animals as compared to disease control. mRNA expression of MAFbx and MHCβ There was a significant relative fold increase in the MAFbx level in the disease control animals as compared to the level of MAFbx in the cilnidipine treated animals. There was a significant increase in the levels of the MHC β in the disease control animals as compared to the animals treated with cilnidipine.