Dottorato in BIOCHIMICA

Titolo della tesi: Natural compounds as modulators of STAT3-mediated chemical carcinogenesis

Cancer is one of the diseases categorized as non-communicable. This disease is closely linked to lifestyle and environmental factors. In this work, we investigated whether β-Hexachlorocyclohexane (β-HCH), an organochlorine environmental pollutant, can drive the three stages of carcinogenesis and the process of resistance to anticancer drugs. We used the BEAS-2B cell line to study carcinogenesis. Instead, the MCF7, H358, LNCaP, and Hepg2 cell lines were employed to study the drug resistance that these cell lines develop against three kinase inhibitor: Lapatinib, Dasatinib, and AZD1480. Results have demonstrated that β-HCH can drive all three stages of carcinogenesis and is involved in chemoresistance processes. In addition, the STAT3 protein, which we already knew to be the hub of the cellular pathways triggered by β-HCH, has also proven to be crucial in the drug resistance induced by the pollutant. The identification of this crucial role of STAT3, has allowed us to identify inexpensive, readily available natural substances capable of modulating the actions of the pollutant. A proper diet or dietary supplementation is the quickest and most cost-effective means. For this reason, we have tested natural compounds, including STAT3 inhibitors, derived from a dietary supplement from olive mill wastewater and whole tomato. The solution obtained from the dietary supplement (TOBC) has been tested on the androgen-sensitive human prostate adenocarcinoma cell line LNCaP. In this cell line, it has been demonstrated that TOBC can counteract all the cellular activities of β-HCH (AR activation, AhR activation, genotoxic damage, ROS production, impact on the cell cycle and apoptosis, etc.). Furthermore, TOBC has been tested on MCF7, H358, LNCaP, and HepG2 cell lines to assess its protective action against drug resistance. These results on TOBC are crucial, as they lay the foundation to support public health policies for prevention and care for polluted populations.