Repurposing HIV protease inhibitors as senotherapeutic agents in cervical cancer: Dual targeting of CDK1/6-cell cycle arrest and p53/p21/p16 signaling axis
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The clinical management of cervical cancer remains constrained by limited therapeutic options and a paucity of targeted pharmacological interventions. Drug repurposing emerges as a promising strategy to expedite oncological therapeutics development. This study systematically investigates the antineoplastic potential of HIV protease inhibitors saquinavir (SQV) and tipranavir (TPV) through multimodal mechanistic validation. In vitro analyses demonstrated dose-dependent inhibition of cervical cancer cell proliferation accompanied by significant upregulation of senescence-associated β-galactosidase (SA-β-Gal) activity. Molecular characterization revealed concomitant activation of senescence-regulatory proteins p53, p21, and p16, suggesting induction of tumor-suppressive senescence pathways. Transcriptomic profiling of inhibitor-treated SiHa cells identified critical cell cycle regulators CDK1 and CDK6, findings corroborated by molecular docking simulations revealing high-affinity binding to cyclin-dependent kinases (-32.0607 to -47.6820 kJ/mol). In vivo validation using xenograft models demonstrated comparable tumor growth inhibition to doxorubicin with preserved host viability and negligible systemic toxicity. Mechanistic integration revealed dual pathway modulation: G1-phase cell cycle arrest mediated through CDK1/6 suppression and coordinated activation of the p53/p21/p16 senescence signaling axis. These findings establish SQV and TPV as multi-targeted senotherapeutic agents, providing preclinical rationale for repurposing HIV antivirals as novel therapeutic strategy against cervical malignancies.