Mahanine Synergistically Enhances Cytotoxicity of 5-fluorouracil Through ROS-mediated Activation of PTEN and p53/p73 in Colon Carcinoma

Apoptosis. 2014 Jan;19(1):149-64. doi: 10.1007/s10495-013-0907-6.

Abstract

5-Fluorouracil (5-FU) alone or in combination with other drugs is the main basis of chemotherapeutic treatment in colorectal cancer although patients with microsatellite instability generally show resistance to 5-FU treatment. The present investigation is focussed on the mechanistic insight of a pure herbal carbazole alkaloid, mahanine, as a single or in combination with 5-FU in colon cancer. We demonstrated that mahanine-induced apoptosis involved reactive oxygen species (ROS)-mediated nuclear accumulation of PTEN and its interaction with p53/p73. Mahanine and 5-FU in combination exerted synergistic inhibitory effect on cell viability. This combination also enhanced ROS production, increased tumour suppressor proteins and suppressed chemo-migration. Taken together, our results revealed that mahanine can be a potential chemotherapeutic agent with efficacy to reduce the concentration of toxic 5-FU in colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects
  • Carbazoles / pharmacology*
  • Carcinoma / drug therapy
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Carcinoma / physiopathology*
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / physiopathology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drug Combinations
  • Drug Synergism
  • Fluorouracil / toxicity*
  • Humans
  • Murraya / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Plant Extracts / pharmacology
  • Reactive Oxygen Species / metabolism*
  • Rutaceae / chemistry
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • Carbazoles
  • DNA-Binding Proteins
  • Drug Combinations
  • Nuclear Proteins
  • Plant Extracts
  • Reactive Oxygen Species
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • mahanine
  • p73 protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Fluorouracil