Resveratrol and curcumin synergistically induces apoptosis in cigarette smoke condensate transformed breast epithelial cells through a p21(Waf1/Cip1) mediated inhibition of Hh-Gli signaling

Int J Biochem Cell Biol. 2015 Sep:66:75-84. doi: 10.1016/j.biocel.2015.07.009. Epub 2015 Jul 23.


Combination therapy using two or more small molecule inhibitors of aberrant signaling cascade in aggressive breast cancers is a promising therapeutic strategy over traditional monotherapeutic approaches. Here, we have studied the synergistic mechanism of resveratrol and curcumin induced apoptosis using in vitro (cigarette smoke condensate mediated transformed breast epithelial cell, MCF-10A-Tr) and in vivo (tumor xenograft mice) model system. Resveratrol exposure increased the intracellular uptake of curcumin in a dose dependent manner and caused apoptosis in MCF-10A-Tr cells. Approximately, ten fold lower IC50 value was noted in cells treated with the combination of resveratrol (3μM) and curcumin (3μM) in comparison to 30μM of resveratrol or curcumin alone. Resveratrol+curcumin combination caused apoptosis by increasing Bax/Bcl-xL ratio, Cytochrome C release, cleaved product of PARP and caspase 3 in cells. Interestingly, this combination unaltered the protein expressions of WNT-TCF and Notch signaling components, β-catenin and cleaved notch-1 val1744, respectively. Furthermore, the combination also significantly decreased the intermediates of Hedgehog-Gli cascade including SMO, SHH, Gli-1, c-MYC, Cyclin-D1, etc. and increased the level of p21(Waf/Cip1) in vitro and in vivo. A significant reduction of Gli- promoter activity was noted in combinational drug treated cells in comparison to individual drug treatment. Un-alteration of the expressions of the above proteins and Gli1 promoter activity in p21(Waf/Cip1) knockout cells suggests this combination caused apoptosis through p21(Waf/Cip1). Thus, our findings revealed resveratrol and curcumin synergistically caused apoptosis in cigarette smoke induced breast cancer cells through p2(Waf/Cip1) mediated inhibition of Hedgehog-Gli cascade.

Keywords: Combination therapy; Curcumin; Hh-Gli Signaling; MCF-10A-Tr; Resveratrol; p21(Waf/Cip1).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line
  • Cell Transformation, Neoplastic / drug effects
  • Curcumin / pharmacology*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Drug Synergism
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Hedgehog Proteins / metabolism*
  • Humans
  • Immunoblotting
  • Mice, Inbred BALB C
  • Microscopy, Fluorescence
  • RNA Interference
  • Resveratrol
  • Signal Transduction / drug effects
  • Smoke
  • Stilbenes / pharmacology*
  • Tobacco / chemistry
  • Tobacco / toxicity
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Xenograft Model Antitumor Assays
  • Zinc Finger Protein GLI1
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / metabolism


  • Antineoplastic Agents
  • BAX protein, human
  • BCL2L1 protein, human
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • GLI1 protein, human
  • Hedgehog Proteins
  • SHH protein, human
  • Smoke
  • Stilbenes
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Curcumin
  • Resveratrol