Tea tree oil extract causes mitochondrial superoxide production and apoptosis as an anticancer agent, promoting tumor infiltrating neutrophils cytotoxic for breast cancer to induce tumor regression

Amanda M Clark,Chandi Magawa,Adriana Pliego-Zamora,Pauline Low,Max Reynolds,Stephen J Ralph

doi:10.1016/j.biopha.2021.111790

Amanda M Clark, Chandi Magawa + Show 4 more

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https://doi.org/10.1016/j.biopha.2021.111790

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Journal: Biomedicine & Pharmacotherapy	Publication Date: Jun 11, 2021
Citations: 10	License type: cc-by

Affiliation: Griffith University

Abstract

The antitumor activity of the tea tree oil (TTO) derived product, Melaleuca Alternifolia Concentrate (MAC) was characterized mechanistically at the molecular and cellular level. MAC was analyzed for its anticancer activity against human prostate (LNCaP) and breast (MCF-7) cancer cell lines growing in vitro. MAC (0.02–0.06% v/v) dose-dependently induced the intrinsic (mitochondrial) apoptotic pathway in both the LNCaP and MCF-7 cell lines, involving increased mitochondrial superoxide production, loss of mitochondrial membrane potential (MMP), caspase 3/7 activation, as well as the presence of TUNEL+ and cleaved-PARP+ cell populations. At concentrations of 0.01–0.04% v/v, MAC caused cell cycle arrest in the G0/1–phase, as well as autophagy. The in vivo anticancer actions of MAC were examined as a treatment in the FVB/N c-Neu murine model for spontaneously arising breast cancers. Intratumoral MAC injections (1–4% v/v) significantly suppressed tumor progression in a dose-dependent manner and was associated with greater levels of tumor infiltrating neutrophils exhibiting anticancer cytotoxic activity. Induction of breast cancer cell death by MAC via the mitochondrial apoptotic pathway was also replicated occurring in tumors treated in vivo. In conclusion, our data highlights the potential for the Melaleuca-derived MAC product inducing anticancer neutrophil influx, supporting its application as a novel therapeutic agent.

Highlights

Essential oils are natural, volatile and complex mixtures character ized by a strong odor and are formed by aromatic plants as secondary metabolites
The results demonstrate the selective activity of Melaleuca Alternifolia Concentrate (MAC) against human breast and prostate cancer cells in vitro, inducing rapid mitochondrial superoxide production of reactive oxygen species (ROS), caspase-3/7 activation, Poly polymerase (PARP) cleavage, DNA damage and apoptotic cell death via the mitochondrial dependent pathway
MAC, terpinen-4-ol or limonene were examined for their cytotoxicity towards the two human cancer cell lines, LNCaP prostate or MCF-7 breast cancer cells versus the nonmalignant Vero kidney epithelial cells

Summary

Introduction

Volatile and complex mixtures character ized by a strong odor and are formed by aromatic plants as secondary metabolites. Essential oils comprise as little as 20 to over 100 different compounds in vastly differing concentrations. They are typically characterized by two or three major constituents with high concentrations (20–70%), while the remaining compounds are usually only present in trace amounts [1,2,3,4,5,6,7]. The largest class of secondary metabolites present in essentials oils are terpenes and their role and contribution as anticancer agents has been extensively reported and previously reviewed [8,9,10,11,12,13]. The use of essential oils as anticancer therapeutics may not be a conventional

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