An investigation on the bio-therapeutic effects of Ficus carica latex in cancer progression

Human papillomavirus (HPV) remains the central aetiological driver of cervical cancer, yet effective therapeutic options for patients with established HPV-associated disease remain limited. Natural products represent an important but underexplored source of antiviral and anticancer compounds. Ficus carica (fig) latex has historically been used for papillomatous lesions, suggesting a potential biological activity against HPV-related pathologies. However, its mechanistic effects in HPV-transformed cancer models have not been elucidated. This thesis presents the first comprehensive, multi-layered investigation of Ficus carica latex in HPV-positive and HPV-negative cervical cancer systems, integrating phytochemical profiling, 2D functional assays, 3D spheroid and tumour-on-chip models, transcriptomic analysis, and in silico molecular docking. Chemical characterisation demonstrated that Turkish fig latex contains a diverse mixture of triterpenes, flavonoids, and furanocoumarins compound classes known for mitochondrial and immunomodulatory activity. In 2D culture, fig latex exhibited selective cytotoxicity towards HPV-positive cervical cancer cells while sparing normal keratinocytes. Clonogenic assays confirmed long-term growth suppression. RNA-seq analysis revealed a striking immune-restorative signature in HPV-positive cells, including reactivation of antigen-processing pathways (TAP1, B2M, HLA-A) typically suppressed by HPV oncoproteins, whereas HPV-negative cells predominantly activated ER-stress-mediated apoptosis. 3D spheroid experiments reproduced and amplified these findings under physiologically relevant conditions. Latex treatment disrupted spheroid architecture, reduced invasive protrusions, and induced mitochondrial transcriptional reprogramming (MT-ND5, MT-CYB, MT-RNR2). These effects were specific to HPV-positive models, indicating selective mitochondrial vulnerability. In silico docking, the experimental data, showing strong interactions between fig-latex constituents and key targets including HPV E6/E7, Bcl-2, Caspase-3, EGFR, and NF-κB. These results suggest a dual mechanistic model: inhibition of 5 viral oncoprotein functions and restoration of tumour-suppressor and immune pathways, combined with intrinsic mitochondrial apoptosis.

Collectively, this thesis establishes Ficus carica latex as a promising multi-targeted natural product with selective activity against HPV-associated cervical cancer. By integrating chemical, computational, and advanced 3D biological systems, this work provides the first mechanistic foundation for developing fig-latex-derived therapeutics and highlights key pathways for future preclinical and translational investigation.