DOI: 10.4103/jcot.jcot_7_26 ISSN: 3050-5763
Comprehensive Evaluation of SIRT1 as a Therapeutic Target in Metastatic Ovarian Cancer and Multimodel Assessment of its Inhibitor
Sraddhya Roy, Koustav Maiti, Arundhati Roy, Ananya Das, Aparajita Bairagi, Manisha Vernekar, Nabanita Chatterjee, Chandra Sekar Ponnusamy Abstract
Background:
The menace caused by ovarian cancer (OvCa) is developing into an alarming situation globally because of its higher incidence and mortality rates. Despite technological and therapeutic advances, there is an emergency to identify a potent molecular target to combat the disease.
Aim:
In this study, we investigated sirtuin 1 (SIRT1) as a potential target and demonstrated the therapeutic importance of inhibiting SIRT1.
Materials and Methods:
Publicly available datasets were analyzed to evaluate
SIRT1
genetic alterations, expression, and clinical significance in OvCa. Metascape and Gene Set Cancer Analysis were performed to investigate the involvement of
SIRT1
in EMT and PI3K/AKT signaling. Molinspiration and the pkCSM server were implemented to study drug likeness and ADME/T properties of selected ligands, followed by MD simulation of target-ligand interactions. Experimental validations examined the effects of SIRT1 Inhibitor III on OvCa migration and progression.
Results:
SIRT1
genetic alterations are higher in OvCa cases and in
TP53
mutant samples. SIRT1 expression was higher in OvCa tissues and adjacent normal tissues (N = 15). Functional analyses associated
SIRT1
with EMT and PI3K/AKT signaling. SIRT1 Inhibitor III demonstrated the strongest binding affinity toward SIRT1, PI3K, and AKT compared with hyperforin and favorable pharmacokinetic properties, with stable protein-ligand interactions during MD simulations. Experimental validations in SKOV3 cells (IC
50
= 0.1606 μM) showed reduced cellular migration, and in C57BL/6 mice, reduced tumor progression was observed.
Conclusion:
Collectively,
in silico
approaches and experimental validations revealed SIRT1 as a promising therapeutic target and the efficacy of SIRT1 Inhibitor III for OvCa progression.