Inotodiol suppresses proliferation of breast cancer in rat model of type 2 diabetes mellitus via downregulation of β-catenin signaling

Biomed Pharmacother. 2018 Mar;99:142-150. doi: 10.1016/j.biopha.2017.12.084.

Abstract

Breast cancer is amongst the most common cancers causing death of women worldwide. Breast cancer occurrence is more prominent in people with diabetes. A recent trend is management of diabetes and cancer has evolved to be natural remedy including single molecule therapy or combination. In this study, we investigated the effect of inotodiol on breast cancer growth in diabetic conditions. Inotodiol is a lanostane triterpenoid found in natural resources like edible mushroom Inonotus obliquus. We established a rat model of diabetic-breast cancer by treating female Sprague-Dawley rats with streptazotocin (STZ) at 35 mg/kg followed by induction of breast cancer by administration of 7,12-dimethylbenz(a)anthracene (DMBA) at 10 mg/kg. Diabetes development in experimental rats was confirmed by measuring fasting blood glucose levels and oral glucose tolerance test (OGTT), and other biochemical assays were performed. Histological evaluation of pancreas was performed. The proliferation of breast tumor was measured by immunohistochemical staining for PCNA, cleaved-caspase-3 and TUNEL staining for apoptosis, and β-catenin. Results of the study demonstrate that inotodiol lowered the blood glucose levels in SD rats as well as reduced plasma levels of cholesterol, triglyceride, and high-density lipoprotein. The tumor proliferation marker PCNA was reduced by inotodiol. It downregulated the expression of β-catenin and its downstream targets (c-Myc and Cyclin D1) followed by apoptosis induction. Conclusively, results suggest that inotodiol regulates blood glucose levels in diabetic rats and then controls proliferation of breast tumor progression by inducing apoptosis via downregulation of β-catenin signaling. It further suggests that inotodiol can be a preventive approach in managing dietary chronic conditions like diabetic-breast cancer.

Keywords: Anti-diabetic; Apoptosis; Breast cancer; Cancer prevention; Chaga mushroom; β-catenin.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • Cell Proliferation / drug effects
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / pathology
  • Disease Models, Animal
  • Down-Regulation* / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glucose Tolerance Test
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Lanosterol / analogs & derivatives*
  • Lanosterol / pharmacology
  • Lanosterol / therapeutic use
  • Mammary Neoplasms, Animal / blood
  • Mammary Neoplasms, Animal / complications*
  • Mammary Neoplasms, Animal / drug therapy*
  • Mammary Neoplasms, Animal / pathology
  • Pancreas / drug effects
  • Pancreas / pathology
  • Rats, Sprague-Dawley
  • Signal Transduction* / drug effects
  • Streptozocin
  • beta Catenin / metabolism*

Substances

  • Blood Glucose
  • Hypoglycemic Agents
  • beta Catenin
  • inotodiol
  • Lanosterol
  • Streptozocin