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Updated: Aug 12, 2025

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Mitochondrial dysfunction and chromatin changes with autophagy-mediated survival in doxorubicin resistant cancer cell

Abhiram Natu1, Aditi Pedgaonkar2, Sanjay Gupta1

  • 1Epigenetics and Chromatin Biology Group, Gupta Lab, Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, MH, India; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, 400094, MH, India.

Biochemical and Biophysical Research Communications
|February 1, 2023
PubMed

Insights

Doxorubicin resistance in cancer involves altered cell metabolism, mitochondrial dysfunction, and activated autophagy. Targeting chromatin modification or autophagy offers new therapeutic strategies for resistant cervical and liver cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Acquired chemoresistance to doxorubicin hinders effective cancer treatment.
  • The precise molecular mechanisms driving doxorubicin resistance are not fully understood.

Purpose of the Study:

  • To elucidate the survival mechanisms in doxorubicin-resistant cervical and liver cancer cells.
  • To explore alternative treatment strategies for overcoming doxorubicin resistance.

Main Methods:

  • Doxorubicin-resistant cancer cell lines were generated through incremental drug exposure.
  • Transcriptome analysis identified key molecular pathways affected by drug resistance.
  • Histone deacetylase inhibitors (HDACi) and autophagy inhibitors were used to test therapeutic interventions.

Main Results:

  • Doxorubicin resistance was associated with downregulated energy production pathways (glycolysis, oxidative phosphorylation, mTOR signaling), leading to slow proliferation and mitochondrial alterations.
  • Resistant cells exhibited hypo-acetylation of chromatin.
  • Pre-treatment with HDAC inhibitors sensitized resistant cells to doxorubicin, increasing drug accumulation and apoptosis.
  • Autophagy was activated in resistant cells, functioning as a pro-survival mechanism.

Conclusions:

  • Doxorubicin-resistant cancer cells survive through mitochondrial dysfunction, altered chromatin states, and pro-survival autophagy.
  • Combinatorial therapy targeting chromatin modification (HDAC inhibitors + doxorubicin) or autophagy inhibition presents a promising approach against doxorubicin-resistant cancers.
Keywords:
AutophagyCancerDoxorubicinHypoacetylationMitochondria

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