Fermented Mangosteen (Garcinia mangostana L.) Supplementation in the Prevention of HPV-Induced Cervical Cancer: From Mechanisms to Clinical Outcomes

SIMPLE SUMMARY: Human papillomavirus (HPV) is connected with virtually all cases of cervical cancer. The viral infection-associated chronic inflammation, oxidative stress, and alterations in apoptosis have been considered as leading risk factors for carcinogenesis in humans. In an observational clinical study, we identified oxidative markers and the cervical/circulating ligands of TNF-alpha-induced apoptosis involved in HPV-associated cervical carcinogenesis. In the following clinical trial, 250 females infected with high-cancer-risk HPV16/18 (healthy and pre-cancerous) were recruited into a placebo-controlled clinical study of supplementation with fermented mangosteen (FM, 28g/day, daily) for three months. Our findings indicate that FM, and not a placebo, in combination with routine anti-viral therapy, could prevent, slow down, or even interrupt HPV-associated cervical carcinogenesis, mainly through the suppression of leukocyte recruitment into infected tissue, through anti-inflammatory effects, and through the restoration of nitric oxide metabolite-initiated TRAIL-dependent apoptosis. ABSTRACT: In the observational clinical study, we identified the oxidative markers of HPV-associated cervical carcinogenesis and the local/circulating ligands of TNF-alpha-induced apoptosis. Cervical biopsies of 196 females infected with low-cancer-risk HPV10/13 or high-cancer-risk HPV16/18 (healthy, pre-cancerous CIN I and CIN II, and CIN III carcinoma) were analysed for OH radical scavenging, catalase, GSH-peroxidase, myeloperoxidase (MPO), nitrate/nitrite, nitrotyrosine, and isoprostane. Ligands of TNF-alpha-dependent apoptosis (TNF-alpha, TRAIL, IL-2, and sFAS) were determined in cervical fluid, biopsies, and serum. Cervical MPO was highly enhanced, while nitrotyrosine decreased in CIN III. Local/circulating TRAIL was remarkably decreased, and higher-than-control serum TNF-alpha and IL-2 levels were found in the CIN I and CIN III groups. Then, 250 females infected with HPV16/18 (healthy and with CIN I and CIN II) were recruited into a placebo-controlled clinical study of supplementation with fermented mangosteen (FM, 28g/day, daily) for three months. Post-trial colposcopy revealed normal patterns in 100% of the FM group versus 62% of the placebo group. Inflammatory cells in cervical fluid were found in 21% of the FM group versus 40% of the placebo group. Locally, FM drastically diminished MPO and NO(2)/NO(3), while it remarkably increased TRAIL. Additionally, FM supplementation normalised serum TRAIL, TNF-alpha, and IL-2.