Evaluation of Sodium Orthovanadate as PTP1B Inhivitor for Treatment of Colon Cancer Associated With Type 2 Diabetes Melitus

Abstract

As per the estimation of International Diabetes Federation, India was the 2nd leading country in top ten highest diabetic prevalent countries in 2017; data showed that India will be the 1st country with highest prevalence of diabetes in 2045. Colon cancer is 4th most common cancer among all the type of cancer with 3rd highest estimated new cases and second highest deaths caused in 2017. Type 2 diabetes mellitus causes hyperglycemia and hyperinsulinemia which forces the insulin acts like insulin like growth factor-1 (IGF-1) and binds it with insulin like growth factor-1 receptor (IGF-1R). Thus, activation of IGF-1R leads to activation of cellular growth pathways resulting into elevated cell growth and proliferation, cell-cell adhesion and angiogenesis and decreases apoptosis which turns into development of cancer growth. Protein tyrosine phosphatase 1b (PTP1b) is nontransmembrane enzyme which alters insulin receptor and insulin receptor substrates resulting into impairment in glucose and lipid metabolism and develops hyperinsulinemia. Along with development of T2DM, PTP1b also activates PI3K-Ras- Raf-MEK1/2-Erk and PI3K-Akt/PKB-mTOR cell signaling pathways which are responsible for cell proliferation, cell differentiation and cell survival; finally in development of cancer.Thus, inhibition of PTP1b can be beneficial in treatment of colon cancer associated with T2DM. Sodium orthovanadate is a competitive inhibitor of PTP1b because of its Phosphatase like structure. Previous studies revealed that, SOV exhibits insulin-mimic and tumor-suppressive effects which can be useful in treatment of diabetes and colon cancer respectively. Despite this, the main objective of the present experiment was to study the possible anti-diabetic, anti-proliferative, anti-angiogenetic and apoptotic effects of SOV and find out the possible mechanism of action. MATERIAL AND METHODS In-vivo studies T2DM was induced by feeding of high fat diet for 2 weeks which included 58% fat, 25%protein and 17% carbohydrate (% of total Kcal ad libitium). After 2 weeks, low dose of streptozotocin (35mg/kg) was given by i.p. route for T2DM induction. After 6 weeks, diabetes was confirmed by checking blood glucose level. For colon cancer induction, DMH was given twice a week for 14 weeks and then for 4 weeks, animals were kept as such for colon cancer induction phase. Colon cancer induction was confirmed by checking blood traces in stool. Treatment of Sodium orthovanadate was started by adding it in drinking water ad libitiumfor 4 weeks. At the end of 28th week, blood was collected and animals were sacrificed for further parameters evaluation. The anti-diabetic effects of Sodium orthovanadate were checked by blood glucose level, OGTT, %HbA1C and rat