Indole-3-Carbinol (I3C) enhances the sensitivity of murine breast adenocarcinoma cells to doxorubicin (DOX) through inhibition of NF-κβ, blocking angiogenesis and regulation of mitochondrial apoptotic pathway

Chem Biol Interact. 2018 Jun 25:290:19-36. doi: 10.1016/j.cbi.2018.05.005. Epub 2018 May 15.


Various epidemiological and preclinical studies have already established the cancer chemopreventive potential of naturally occurring glucosinolate breakdown product Indole-3-Carbinol (I3C) as well as its abilities to induce selective cell death towards malignant cell. Therefore, the objective of the present study is to improve the therapeutic efficacy and prevention of doxorubicin (DOX)-induced toxicity, by the concurrent use of Indole-3-Carbinol (I3C). In this study, I3C was administered (20 mg/kg b.w., p.o.) to breast adenocarcinoma (Ehrlich ascites carcinoma) induced solid tumor bearing mice alone as well as in combination with DOX (5 mg/kg b.w., i.p.) in concomitant and pretreatment schedule. The results showed that concurrent administration of I3C and DOX significantly (P < 0.05) improved therapeutic efficacy as evidenced by reduction of tumor size and enhancement of host survivability. Oral administration of I3C significantly (P < 0.05) inhibited the expression of NF-κβ in both tumor cells and cardiac tissue as well as maximizes the therapeutic outcome in terms of tumor cell killing and toxicity. In addition, I3C sensitized tumor cells to DOX-therapy by down-regulating the expression of anti-apoptotic protein Bcl-2 and by up-regulating molecules like Bax, cytochrome c, caspases, which led to PARP cleavage and apoptosis. Significant inhibition of angiogenesis along with reduction in the serum levels of VEGF-A and MMP-9 further contribute to the sensitization accomplished by I3C. Moreover, we also found that I3C provided additional host survival advantages by attenuated DOX-induced toxicities through modulation of Nrf2/ARE pathway and promoted expression of cytoprotective proteins HO-1, NQO1 and GSTπ in cardiac tissue. In addition, I3C significantly attenuated DOX-induced inflammation by down-regulation of NF-kβ, iNOS, COX-2 and IL-6 in cardiac tissue. Thus, the present study clearly suggested therapeutic benefit of I3C in combination with DOX by augmenting anticancer efficacy and diminishing toxicity to the host.

Keywords: Angiogenesis; Apoptosis; Chemoprotective; DNA damage; Ehrlich ascites carcinoma; Oxidative stress.

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology
  • Anticarcinogenic Agents / therapeutic use
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Down-Regulation / drug effects
  • Doxorubicin / pharmacology*
  • Female
  • Indoles / pharmacology*
  • Indoles / therapeutic use
  • Matrix Metalloproteinase 9 / blood
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neovascularization, Pathologic / drug therapy
  • Oxidative Stress / drug effects
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reactive Oxygen Species / metabolism
  • Transplantation, Heterologous
  • Up-Regulation / drug effects


  • Anticarcinogenic Agents
  • Antineoplastic Agents
  • Indoles
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Doxorubicin
  • indole-3-carbinol
  • Matrix Metalloproteinase 9