Dottorato in FARMACOLOGIA E TOSSICOLOGIA

Titolo della tesi: Characterization of the pharmaco-toxicological properties of natural substances and environmental pollutants by in vitro studies and molecular analysis

In the recent years, a great attention has been devoted to the identification of potential chemopreventive agents able to inhibit, suppress, or reverse tumor development and progression both in healthy people and oncologic patients. Particularly, the natural sesquiterpenes β-caryophyllene and its metabolite β-caryophyllene oxide have been highlighted to possess a safe toxicity profile and multiple biological activities, including genoprotective, cytoprotective, antiproliferative, analgesic, anti-inflammatory, antioxidant, neuroprotective and chemosensitizing ones, and to modulate different intracellular cascades, thus affecting both cancer proliferation and sensitivity to chemotherapy. This evidence strengthens the interest in these natural substances as chemopreventive and chemosensitizing agents towards a number of xenobiotics, including both pollutants and drugs. In my PhD project, I focused my attention on the damage induced by cigarette smoke and lindane (both γ-hexachlorocyclohexane or β-HCH, and β- hexachlorocyclohexane or γ-HCH), hazardous environmental pollutants known to be responsible for cancer initiation and chemoresistance development. Moreover, the ability of the tested substance to sensitize cancer cells to chemotherapy and increase the efficacy of anticancer drugs (especially doxorubicin and sorafenib) has been explored. In these studies, I also evaluated the ability of caryophyllane sesquiterpenes to lower the toxicity of anticancer drugs in noncancerous cells, which represents an important goal of chemotherapy. At last, the cancer suppressive effects of matrices containing caryophyllane sesquiterpenes, particularly extracts and essential oils from the hemp (Cannabis sativa L.) inflorescences, to establish the contribution of caryophyllane sesquiterpene to the activity of the phytocomplex, and their ability to potentiate the activity of the major meroterpenoids (or cannabinoids). The studies have been performed using different cancerous and noncancerous in vitro models of the gastro-intestinal tract, along with breast and airway. As mechanistic hypothesis, I investigated the ability of caryophyllane sesquiterpenes to counteract the genetic damage induced by the tested pollutants, in terms of phosphorylation of H2AX histone (γH2AX), which is considered as a powerful tool to monitor DNA damage in translational cancer research. Also, the ability of the test substances to control the function and expression of ATP-binding cassette (ABC) transporters, responsible for drug efflux from cells and involved in multidrug resistance has been explored. At last, I explored the modulation of signal transducer and activator of transcription 3 (STAT3) cascade, known to control cell survival and cancer progression, thus representing chemoprevention mechanisms. Although further in vivo studies are required in confirmation, our results strengthen the interest in caryophyllane sesquiterpenes as dual acting chemopreventive and chemosensitizing agents, able to protect noncancerous cells from toxicants and to sensitize cancer cells to chemotherapy, thus suggesting a possible future application as boosting agents in healthy subjects and as adjuvant strategies for cancer patients.