Understanding the mechanistic aspect of thymoquinone in breast cancer by employing different nanocomposites

Recently, phytochemicals have attracted attention due to their antioxidant, haemo-protective and anti-cancer properties. As compared to most Food and Drug Administration (FDA) approved cancer therapeutic drugs, phytochemicals have shown specificity towards cancer cells and have little or no adverse effects on healthy cells. One such phytochemical is Thymoquinone (TQ), a quinone based constituent in volatile oils of Black cumin. Its anti-oxidant and anti-inflammatory effect has been reported in various disease models including encephalomyelitis, diabetes, asthma and cancer. While TQ has been shown to affect cancer cell motility and migration, a distinct signalling pathway responsible for this effect has yet to be identified for the effect of TQ on motility and migration of cancer cells. The focus of this research was to elucidate the mechanism by which TQ interacts with the extracellular adhesion proteins of the cells involved in the motility, migration and cancer metastasis. The results revealed that TQ at low concentrations reduces the expression of E-cadherin (E-cad) which is a transmembrane protein responsible for cell-cell adhesion. The reduction of E-cad in cancer is a hallmark of epithelial to mesenchymal transition (EMT). During EMT, epithelial cells lose their adhesion proteins to detach from the tumour, exhibiting mesenchymal phenotype, entering the blood, and metastasize to its secondary target site. This poses a risk under in vivo scenario since TQ exhibits low bioavailability in the body and undergoes rapid elimination. Hence, the effective concentration of phytochemicals in the body are often much lower than when encountering the target cells in vivo. To address the issues of degradation, low bioavailability and low solubility of TQ in aqueous media, nano-based solutions were utilised. Three different types of nanoparticles were used to improve the therapeutic efficacy of TQ viz. dendrimers, nanosuspension and polymer-amino acid gold composite. All three nano-based systems showed significantly higher therapeutic efficacy compared to pristine TQ with increased toxicity due to increase in levels of reactive oxygen species and change in mitochondrial membrane potential level. In order to understand that the pro- cancerous effect of TQ was due to its lower concentration; an experiment was conducted in which the nanoformulations were titrated on the basis of the viability of TQ at a sub-lethal concentration. The results of this experiment suggest that low concentration of TQ is responsible for activation of EMT in cancer cells which can be potentially resolved by the use of different nanoparticulate based formulations to increase its therapeutic efficacy against breast cancer