Resensitization of Akt Induced Docetaxel Resistance in Breast Cancer by 'Iturin A' a Lipopeptide Molecule from Marine Bacteria Bacillus megaterium

Sci Rep. 2017 Dec 11;7(1):17324. doi: 10.1038/s41598-017-17652-z.

Abstract

Development of the resistance is the major problem in cancer therapy. Docetaxel is a taxol alkaloid that is frequently used in metastatic breast cancer. However, resistance often limits the usefulness of this drug in many breast cancer patients. Manipulation of resistant cells to re-sensitize to the therapeutic effect of docetaxel is current strategy to overcome this problem. Here, we have introduced 'Iturin A' as a potent chemosensitizer in docetaxel resistant breast cancer cells. Combination of Iturin A and docetaxel treatment significantly hampered the proliferation of docetaxel resistant MDA-MB-231 and MDA-MB-468 breast cancer cells. Cell cycle analysis also showed massive amount of apoptotic population (Sub G0/G1) in combination therapy. A number of apoptotic and anti-apoptotic proteins were significantly altered in dual drug treated groups. Caspase 3 dependent cell death was observed in dual treatment. Molecular mechanism study showed that over-expression of Akt and its downstream signaling pathway was associated with docetaxel resistance. Iturin A significantly reduced Akt signaling pathway in resistant cells. This mechanistic action might be the reason behind the chemo-sensitization effect of Iturin A in docetaxel resistant breast cancer cells. In conclusion, Iturin A resensitized the resistant breast cancer cells to docetaxel therapy by inhibiting Akt activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Bacillus megaterium / chemistry*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Docetaxel / pharmacology*
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lipopeptides / pharmacology*
  • Peptides, Cyclic / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • Tumor Cells, Cultured

Substances

  • Antifungal Agents
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Lipopeptides
  • Peptides, Cyclic
  • Docetaxel
  • iturin A
  • Proto-Oncogene Proteins c-akt