Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma

Suchisnigdha Datta; Anupam Bishayee; Dona Sinha

doi:10.3389/fphar.2023.1176819

Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma

Front Pharmacol. 2023 May 25:14:1176819. doi: 10.3389/fphar.2023.1176819. eCollection 2023.

Authors

Suchisnigdha Datta¹, Anupam Bishayee², Dona Sinha¹

Affiliations

¹ Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, Kolkata, West Bengal, India.
² College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States.

Abstract

Constitutive activation of nuclear factor erythroid 2-related factor 2 (NRF2) is pivotal in bestowing therapy resistance in cancer cells. Several phytochemicals have been reported with the potential of modulating NRF2. Therefore, it was hypothesized that NRF2-deregulated chemoresistance in lung adenocarcinoma (LUAD) may be counteracted by theaflavin-rich black tea (BT). A non-responsive LUAD cell line, A549, was the best sensitized towards cisplatin upon pre-treatment with BT. BT-mediated NRF2 reorientation was observed to be dependent on concentration and duration of treatment as well as on the mutational profile of NRF2 in A549 cells. Transient exposure of low-concentration BT hormetically downregulated NRF2, its downstream antioxidants, and drug transporter. BT also influenced the Kelch-like ECH-associated protein (KEAP1)-dependent cullin 3 (Cul3) and KEAP-1-independent signaling through epidermal growth factor receptor (EGFR) - rat sarcoma virus (RAS) - rapidly accelerated fibrosarcoma (RAF) - extracellular signal-regulated kinase 1/2 (ERK) - matrix metalloproteinase (MMP)-2 and MMP-9. The realignment of NRF2 in KEAP1-suppressed A549 cells enhanced the chemotherapeutic outcome. But a higher concentration of the same BT surprisingly upregulated NRF2 and its transcriptional targets with a subsequent decrease in the NRF2-regulatory machinery in NCI-H23 cells (a KEAP1-overexpressed LUAD cell line), ultimately resulting in a better anticancer response. The BT-mediated bidirectional NRF2 modulation was reconfirmed upon comparison with the action of a pharmacological NRF2 inhibitor, ML-385, in A549 and a known NRF2 activator, tertiary-butylhydroquinone, in NCI-H23 respectively. BT-mediated regulation of NRF2-KEAP1 and their upstream networks (EGFR/RAS/RAF/ERK) sufficed as a better anticancer agent than synthetic NRF2 modulators. Therefore, BT may be indicated as a potent multi-modal small molecule for increasing drug responsiveness in LUAD cells by maintaining NRF2/KEAP1 axis at an optimum level.

Keywords: KEAP1; NRF2; black tea; chemoresistance; lung adenocarcinoma; redox signaling; treatment.

Grants and funding

This work was financially supported by the Indian Council of Medical Research, India (Grant No. 5/13/155/2012/NCD-III). The Indian authors are indebted to the Director, Chittaranjan National Cancer Institute, Kolkata, India, for providing the infrastructural support.