Ovarian Cancer (OC) is nowadays the 3rd most common gynaecologic cancer worldwide, with a 5-years survival rate lower than 50%. The most frequent OC histological subtype is high grade serous ovarian cancer (HGSOC), responsible for the highest mortality rate of all gynaecologic malignancies since most patients are diagnosed at late stages. Moreover, despite an initial response to chemotherapy agents, tumour relapse frequently occurs within 3 years from surgery, with the development of drug resistance. Hence, the identification of prognostic biomarkers to assess drug response is an evident ad also urgent clinical need. Over the last two decades, the progress in imaging technology led to a great revolution in the biomedical field, which is now benefiting from fluorescence imaging. Specifically, breakthroughs in fluorophore chemistry and the identification of targetable biomarkers represent valuable pharmacological tool for oncologists. The identification and removal of all macroscopic and microscopic tumours to render the patient disease-free represents a huge challenge in OC treatment. Cyclooxygenase (COX)-1 and COX-2 catalyze the rate-limiting step in the conversion of arachidonic acid to PGs [1] and are involved in tumour progression by inducing proliferation, invasion, and metastasis formation [2]. HGSOC expresses high levels of COX-1 rather than COX-2. Therefore, COX-1 has been recently proposed as an ideal biomarker for the OC.Hence, new compounds as cancer imaging agents and COX-1 inhibitors, each bearing fluorochromes with different fluorescence features, were projected, synthesized, and in vitro and in vivo pharmacologically evaluated. Two of these compounds N-[4-(9-dimethylimino-9Hbenzo[a]phenoxazin-5-ylamino) butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride (RR11) and 3-(6-(4-(2-(3,4-bis(4-methoxyphenyl)isoxazole-5-yl)acetamido)butyl)amino-6-oxohexyl)-2- [7-(1,3-dihydro1,1-dimethyl-3-ethyl 2H-benz[e]indolin-2-yl-idene)-1,3,5-heptatrienyl]-1,1-dimethyl-3-(6-carboxilato-hexyl)- 1H-benz[e]indolium chloride (MSA14) were found to be potent COX-1 inhibitors. The COX-1 IC50 values were 0.032 and 0.087 µM for RR11 and MSA 14, respectively, whereas the COX-2 IC50 for RR11 is 2.4 µM while MSA 14 did not inhibit COX-2 even at a 50 µM. Structure-based virtual screening (SBVS) performed with the Fingerprints for Ligands and Proteins (FLAP) software allowed both to differentiate highly active compounds from less active and inactive structures and to define their interactions inside the substrate-binding cavity of hCOX1 [1, 2]. Fluorescent probes RR11 and MSA14 were used for preliminary near-infrared (NIR) fluorescent imaging (FLI) in OVCAR-3 and SKOV-3 xenograft models and the results of this study will be presented.

Cyclooxygenase-1 Inhibition: A Promising Theragnostic Approach for Ovarian Cancer

Morena Miciaccia;Savina Ferorelli;Roberta Solidoro;Maria Grazia Perrone;Antonio Scilimati
2023-01-01

Abstract

Ovarian Cancer (OC) is nowadays the 3rd most common gynaecologic cancer worldwide, with a 5-years survival rate lower than 50%. The most frequent OC histological subtype is high grade serous ovarian cancer (HGSOC), responsible for the highest mortality rate of all gynaecologic malignancies since most patients are diagnosed at late stages. Moreover, despite an initial response to chemotherapy agents, tumour relapse frequently occurs within 3 years from surgery, with the development of drug resistance. Hence, the identification of prognostic biomarkers to assess drug response is an evident ad also urgent clinical need. Over the last two decades, the progress in imaging technology led to a great revolution in the biomedical field, which is now benefiting from fluorescence imaging. Specifically, breakthroughs in fluorophore chemistry and the identification of targetable biomarkers represent valuable pharmacological tool for oncologists. The identification and removal of all macroscopic and microscopic tumours to render the patient disease-free represents a huge challenge in OC treatment. Cyclooxygenase (COX)-1 and COX-2 catalyze the rate-limiting step in the conversion of arachidonic acid to PGs [1] and are involved in tumour progression by inducing proliferation, invasion, and metastasis formation [2]. HGSOC expresses high levels of COX-1 rather than COX-2. Therefore, COX-1 has been recently proposed as an ideal biomarker for the OC.Hence, new compounds as cancer imaging agents and COX-1 inhibitors, each bearing fluorochromes with different fluorescence features, were projected, synthesized, and in vitro and in vivo pharmacologically evaluated. Two of these compounds N-[4-(9-dimethylimino-9Hbenzo[a]phenoxazin-5-ylamino) butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride (RR11) and 3-(6-(4-(2-(3,4-bis(4-methoxyphenyl)isoxazole-5-yl)acetamido)butyl)amino-6-oxohexyl)-2- [7-(1,3-dihydro1,1-dimethyl-3-ethyl 2H-benz[e]indolin-2-yl-idene)-1,3,5-heptatrienyl]-1,1-dimethyl-3-(6-carboxilato-hexyl)- 1H-benz[e]indolium chloride (MSA14) were found to be potent COX-1 inhibitors. The COX-1 IC50 values were 0.032 and 0.087 µM for RR11 and MSA 14, respectively, whereas the COX-2 IC50 for RR11 is 2.4 µM while MSA 14 did not inhibit COX-2 even at a 50 µM. Structure-based virtual screening (SBVS) performed with the Fingerprints for Ligands and Proteins (FLAP) software allowed both to differentiate highly active compounds from less active and inactive structures and to define their interactions inside the substrate-binding cavity of hCOX1 [1, 2]. Fluorescent probes RR11 and MSA14 were used for preliminary near-infrared (NIR) fluorescent imaging (FLI) in OVCAR-3 and SKOV-3 xenograft models and the results of this study will be presented.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/420170
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