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Bioactive black tea phytochemicals partially influenced doxorubicin sensitivity by modulation of NRF2-regulatory

Suchisnigdha Datta1, Anupam Bishayee2, Dona Sinha1

  • 1Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, Kolkata, 700 026, West Bengal, India.

Journal of Ayurveda and Integrative Medicine
|February 7, 2026
PubMed
Abstract

Insights

Black tea (BT) phytochemicals sensitized doxorubicin-resistant lung cancer cells by modulating non-canonical nuclear factor erythroid 2-related factor-2 (NRF2) regulators. This study found BT improved drug retention and partially restored chemotherapy responsiveness in resistant lung adenocarcinoma cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Lung cancer therapy resistance is frequently linked to dysfunctional redox-regulatory pathways involving nuclear factor erythroid 2-related factor-2 (NRF2) and Kelch-like ECH-associated protein1 (KEAP1).
  • Understanding the modulation of non-canonical NRF2 regulators is crucial for overcoming drug resistance in lung adenocarcinoma.

Purpose of the Study:

  • To investigate the efficacy of black tea (BT) phytochemicals, specifically theaflavins, in sensitizing doxorubicin (Dox)-resistant lung adenocarcinoma cells.
  • To explore the impact of BT on non-canonical NRF2 regulators in overcoming multidrug resistance (MDR).

Main Methods:

  • Utilized assays for multidrug resistance (MDR), DNA damage (comet assay), cell cycle analysis, and protein expression (western blot, immunocytochemistry).
  • Investigated the role of non-canonical NRF2 regulators and their interaction with NRF2 and KEAP1 in response to BT and Dox treatment.

Main Results:

  • Black tea pretreatment followed by doxorubicin partially reversed Dox resistance in A549 cells by enhancing drug uptake and reducing MDR pump expression.
  • The combination therapy induced DNA damage, cytotoxicity, and reduced invasiveness, while suppressing key proteins like EGFR and Bcl-2.
  • BT modulated non-canonical NRF2 activators (p21, APE1) and repressors (FOXO3, p53, GSK3β, RXR) in a cell-specific manner, affecting NRF2 regulator co-localization.

Conclusions:

  • Black tea improves doxorubicin retention and responsiveness in A549 lung adenocarcinoma cells.
  • BT selectively suppresses NRF2, re-stabilizes KEAP1-independent NRF2 regulators, and partially restores Dox sensitivity in resistant cells.
Keywords:
A549Black tea phytochemicalsDoxorubicin resistance reversalLung cancerNCI–H23Non-canonical NRF2 regulators

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