Sensitizing Triple Negative Breast Cancer to Tamoxifen Chemotherapy via a Redox-Responsive Vorinostat-containing

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Weina Ma1,2,3, Jingjing Sun1,2, Jieni Xu1,2

  • 1Center for Pharmacogenetics.

Theranostics
|March 21, 2020
PubMed

Insights

This study developed a novel nanocarrier for dual drug delivery, effectively re-sensitizing triple-negative breast cancer (TNBC) to tamoxifen therapy by restoring estrogen receptor alpha expression. This combination therapy shows significant promise for treating aggressive TNBC.

Area of Science:

  • Oncology
  • Nanotechnology
  • Pharmacology

Background:

  • Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its aggressive nature and lack of targeted therapy options.
  • Existing treatments for TNBC are limited by the absence of specific receptor targets, necessitating novel therapeutic strategies.
  • Vorinostat (SAHA), a pan-HDAC inhibitor, has shown potential in reactivating silenced genes, including the estrogen receptor alpha (ERα).

Purpose of the Study:

  • To investigate the efficacy of Vorinostat (SAHA) in re-expressing functional estrogen receptor alpha (ERα) in TNBC cells.
  • To evaluate the synergistic antitumor activity of SAHA in combination with tamoxifen (TAM).
  • To develop and assess a novel SAHA prodrug-based nanocarrier for co-delivery of SAHA and TAM for enhanced combination therapy.

Main Methods:

  • A polymeric nanocarrier (POEG-co-PVDSAHA) was synthesized, incorporating SAHA via a redox-responsive disulfide linkage.
  • The re-expression of ERα and its target genes was analyzed in TNBC cell lines upon treatment with free SAHA and the nanocarrier.
  • Cytotoxicity and in vivo antitumor activity were evaluated using MTT assays and a murine breast cancer model (4T1.2), respectively.

Main Results:

  • Both free SAHA and the POEG-co-PVDSAHA nanocarrier successfully induced re-expression of functional ERα in TNBC cells, potentially sensitizing them to TAM.
  • The developed nanocarrier effectively formulated and co-delivered TAM, exhibiting enhanced and synergistic cytotoxicity against TNBC cell lines compared to individual drugs or control carriers.
  • In vivo studies demonstrated significantly improved antitumor efficacy with TAM co-delivered via POEG-co-PVDSAHA micelles compared to other treatment groups.

Conclusions:

  • The SAHA prodrug-based dual-functional nanocarrier system provides an effective strategy for re-sensitizing TNBC to tamoxifen-based therapy.
  • This co-delivery approach holds promise for improving treatment outcomes in patients with aggressive triple-negative breast cancer.
  • The developed nanocarrier system offers a simplified yet potent method for combination therapy in TNBC.
Keywords:
co-deliveryprodrug micellesredox responsivetamoxifenvorinostat

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