Anticancer activity of Bacopa monnieri through apoptosis induction and mitophagy-dependent NLRP3 inflammasome inhibition in oral squamous cell carcinoma

Soumya Ranjan Mishra; Bishnu Prasad Behera; Vineet Kumar Singh; Kewal Kumar Mahapatra; Deepak Mundkinajeddu; Deeksha Bhat; Aruna Mukti Minz; Gautam Sethi; Thomas Efferth; Surajit Das; Sujit Kumar Bhutia

doi:10.1016/j.phymed.2023.155157

Anticancer activity of Bacopa monnieri through apoptosis induction and mitophagy-dependent NLRP3 inflammasome inhibition in oral squamous cell carcinoma

Phytomedicine. 2024 Jan:123:155157. doi: 10.1016/j.phymed.2023.155157. Epub 2023 Oct 21.

Affiliations

¹ Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India.
² Research and Development Department, Natural Remedies Pvt. Ltd, India.
³ Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India; Current affiliation: Department of Agriculture and Allied Sciences (Zoology), C. V Raman Global University, Bhubaneswar, 752054, Odisha, India.
⁴ Department of Pathology, Ispat General Hospital, Rourkela, India.
⁵ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
⁶ Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, 55128 Mainz, Germany.
⁷ Laboratory of Environmental Microbiology and Ecology, Department of Life Science, National Institute of Technology Rourkela, 769008, Odisha, India.
⁸ Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology, Rourkela, 769008, Odisha, India. Electronic address: sujitb@nitrkl.ac.in.

PMID: 37951147
DOI: 10.1016/j.phymed.2023.155157

Abstract

Background: Bacopa monnieri (BM) is traditionally used in human diseases for its antioxidant, anti-inflammatory and neuroprotective effects. However, its anticancer potential has been poorly understood.

Aim: The aim of this study was to explore the detailed anticancer mechanism of BM against oral cancer and to identify the bioactive BM fraction for possible cancer therapeutics.

Results: We performed bioactivity-guided fractionation and identified that the aqueous fraction of the ethanolic extract of BM (BM-AF) had a potent anticancer potential in both in vitro and in vivo oral cancer models. BM-AF inhibited cell viability, colony formation, cell migration and induced apoptotic cell death in Cal33 and FaDu cells. BM-AF at low doses promoted mitophagy and BM-AF mediated mitophagy was PARKIN dependent. In addition, BM-AF inhibited arecoline induced reactive oxygen species production in Cal33 cells. Moreover, BM-AF supressed arecoline-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation through mitophagy in Cal33 cells. The in vivo antitumor effect of BM-AF was further validated in C57BL/6J mice through a 4-nitroquinolin-1-oxide and arecoline-induced oral cancer model. The tumor incidence was significantly reduced in the BM-AF treated group. Further, data obtained from western blot and immunohistochemistry analysis showed increased expression of apoptotic markers and decreased expression of inflammasome markers in the tongue tissue obtained from BM-AF treated mice in comparison with the non-treated tumor bearing mice.

Conclusion: In conclusion, BM-AF exhibited potent anticancer activity through apoptosis induction and mitophagy-dependent inhibition of NLRP3 inflammasome activation in both in vitro and in vivo oral cancer models. Moreover, we have investigated apoptosis and mitophagy-inducing compounds from this plant extract having anticancer activity against oral cancer cells.

Keywords: Apoptosis; Bacopa monnieri; Mitophagy; NLRP3 inflammasome; Oral cancer.

MeSH terms

Animals
Apoptosis
Arecoline / pharmacology
Bacopa* / metabolism
Carcinoma, Squamous Cell* / drug therapy
Head and Neck Neoplasms*
Humans
Inflammasomes / metabolism
Mice
Mice, Inbred C57BL
Mitophagy
Mouth Neoplasms* / drug therapy
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Reactive Oxygen Species / metabolism
Squamous Cell Carcinoma of Head and Neck

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Arecoline
Reactive Oxygen Species