Soprano, Maria
(2014)
Study of anti-tumoral activity of HIV-Protease Inhibitor nelfinavir and identification of new nelfinavir-derivative compounds.
[Tesi di dottorato]
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
Study of anti-tumoral activity of HIV-Protease Inhibitor nelfinavir and identification of new nelfinavir-derivative compounds |
| Autori: |
| Autore | Email |
|---|
| Soprano, Maria | mariarma2@libero.it |
|
| Data: |
25 Marzo 2014 |
| Numero di pagine: |
114 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
Medicina Molecolare e Biotecnologie Mediche |
| Scuola di dottorato: |
Medicina molecolare |
| Dottorato: |
Oncologia ed endocrinologia molecolare |
| Ciclo di dottorato: |
26 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| Santoro, Massimo | masantor@unina.it |
|
| Tutor: |
| nome | email |
|---|
| Illario, Maddalena | [non definito] |
|
| Data: |
25 Marzo 2014 |
| Numero di pagine: |
114 |
| Parole chiave: |
Nelfinavir; breast cancer; reactive oxygen species |
| Settori scientifico-disciplinari del MIUR: |
Area 06 - Scienze mediche > MED/06 - Oncologia medica |
[error in script]
[error in script]
| Depositato il: |
11 Apr 2014 10:48 |
| Ultima modifica: |
12 Nov 2015 02:00 |
| URI: |
http://www.fedoa.unina.it/id/eprint/9661 |
Abstract
Human Immunodeficiency Virus-Protease Inhibitors (HIV-PIs) are peptidomimetic drugs used in AIDS therapy to inhibit HIV infection by blocking viral protease. The advent of these drugs has led to a reduced incidence of HIV-associated tumors, particularly Kaposi’s sarcoma, non-Hodgkin’s lymphoma and cervical cancer. Many studies have also reported an anti-proliferative non-virological action of HIV-PIs in HIV-free models leading them to be further investigated as anti-cancer drugs. In particular HIV-PIs affect several pathways involved in tumor-cell proliferation and survival, angiogenesis, invasion, inflammation, and antitumor immunity in HIV-free models.
The most effective anti-cancer HIV-PIs is nelfinavir, that is in clinical trial for several tumor types, thus encouraging the study of the intracellular pathways at the basis of their anti-tumor activity. The anti-tumoral effects of nelfinavir have been related to inhibition of Akt activation, but to date the molecular mechanism at the basis of anti-cancer activity in breast cancer is poorly understood.
My results suggest an anti-proliferative activity of nelfinavir in a panel of cancer cell lines. In particular, nelfinavir induces apoptosis and necrosis in breast cancer cell lines such as MDA-MB231 and MCF-7 cells by affecting cell cycle in a cell line dependent way. The anti-tumor activity of nelfinavir is linked to the perturbation of cellular redox state; resulting in an increase of intracellular reactive oxygen species (ROS) production in breast cancer cells but not in normal breast epithelial cells. Nelfinavir treated tumor cells show also a downregulation of akt pathway due to the disruption of akt-Heat Shock Protein 90 kDa (HSP90) complex that is induced by nelfinavir and subsequent degradation of akt via proteasome. These effects result to be ROS dependent. Since treatment with anti-oxidant free radical scavenger tocopherol restores akt expression levels as well as viability of nelfinavir-untrated cells, the increase of ROS production represents the main and necessary molecular mechanism to induce cell death in breast cancer cell lines. The anti-cancer effectiveness of nelfinavir has motivated its use as lead compound in this study to design novel anti-tumoral compounds. Primary screening has led to the identification of novel nelfinavir-derivative (4n) with a high anti-cancer efficacy (IC50 50nM), that is a promising molecule to further evaluate for cancer therapy.
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