Punziano, Carolina (2025) Induction of Ferroptosis/Apoptosis by Dimethyl Fumarate in Cervical Cancer cell models through Modulation of Redox-related Pathways. [Tesi di dottorato]

	Documento PDF Carolina_Punziano_37_Completo.pdf Visibile a [TBR] Amministratori dell'archivio Download (1MB) | Richiedi una copia
	Documento PDF Carolina_Punziano_37_Parziale.pdf Visibile a [TBR] Amministratori dell'archivio Download (1MB) | Richiedi una copia

Abstract

About 5% of all human cancers are caused by high-risk human papillomaviruses (HR-HPVs) worldwide; in particular these include the bulk of cervical cancers (>99%) and about 70% of oropharyngeal cancers. Although preventive vaccinations against HPV infection are available, there is an increase in the rate of invasive cervical cancers in last decades. The main etiological factor for cervical cancer progression is represented by a persistent infection of HR-HPVs. HPV-mediated transformation relies on viral proteins that by interacting with several proteins of the host cells dysregulate pathways essential to prevent tumor progression. Long-infection period triggers immortalization and eventually transformation process of infected cells. The conventional treatments for cervical cancers are surgery, radiation therapy and/or chemotherapy. The most effective chemotherapy is based on platinum-drugs, like cisplatin, which may be used either alone or in conjunction with radiation therapy. Treatment failure is frequently observed in cervical cancer. Indeed, after the standard therapy the recurrence is elevated, depending on the stage of the tumor. Dimethyl fumarate (DMF) is an FDA-approved drug and emerging studies suggest that DMF also exerts an anti-tumor activity in some cancers. Therefore, in this study we explored the DMF effectiveness in cervical cancer cell models. Numerous evidence suggests that ferroptosis, a non-apoptotic iron-dependent lipid peroxidation cell death, could represents a treatment strategy for some cancers. Since it is reported that DMF can acts as a pro-ferroptotic agent, first, we tested its capability to activate ferroptosis. The results indicate that high doses of DMF induce ferroptosis in cervical cancer cell lines. Combined therapy is now considered a more efficient approach that can be applied to reduce adverse effects and or overcame treatment resistance. Therefore, we tested if the combination of sub-cytotoxic DMF with sulfasalazine (SAS) or cisplatin (CDDP) increases the potency of the drugs alone. In addition, the effects of these drugs, alone or in combination were tested on three-dimensional (3D) cell cultures (spheroids). Collectively, these data demonstrated that: i) DMF high-dose induces ferroptosis; ii) sub-cytotoxic DMF combined with SAS or Cisplatin enhances cell death compared with respect to drugs alone. Therefore, these results may pave the way to consider DMF as possible therapeutic agent in the treatment/s of cervical tumors.

Downloads

Actions (login required)

Modifica documento