Results from a Dose–Response Study Using 3,3′-Diindolylmethane in the K14-HPV16 Transgenic Mouse Model: Cervical Histology

Abstract

The human papilloma virus is the major cause of cervical cancer. Viral infection initiates cervical intraepithelial neoplasia, which progresses through several stages to cervical cancer. The objective of this study is to identify the minimum effective dose of diindolylmethane that prevents the progression from cervical dysplasia to carcinoma in situ. We document cervical histology in K14-HPV16 mice receiving different doses of diindolylmethane. Urinary diindolylmethane concentrations are reported. Diindolylmethane could enhance the efficacy of human papilloma virus vaccines, creating a new therapeutic use for these vaccines in women already infected with the virus. Five doses (0-2,500 ppm) of diindolylmethane were incorporated into each mouse diet. The reproductive tract was serially sectioned and urine was obtained for analysis of urinary diindolylmethane. The results indicate that 62% of mice receiving 1,000 ppm diindolylmethane remained dysplasia-free after 20 weeks compared with 16% of mice receiving no diindolylmethane and 18% receiving 500 ppm; 1,000 ppm of 3,3 0 -diindolylmethane in the diet completely suppressed the development of cervical cancer. Urinary diindolylmethane levels increased significantly as diindolylmethane in food increased. These findings imply usefulness for diindolylmethane in the search to prevent cervical cancer when used in combination with prophylactic or therapeutic vaccines. Cancer Prev Res; 4(6); 890-6. Ó2011 AACR.

A black raspberry extract inhibits proliferation and regulates apoptosis in cervical cancer cells

“…The K14-HPV16 mouse model is commonly used in studies involving cervical intraepithelial neoplasias and cancer, and provides the essential transition from in vitro to in vivo pre-clinical studies [31,32]. Topical application (locoregional) and dietary administration (systemic) of black raspberries and/or their bioactive components using the K14-HPV16 mouse model would assess the potential efficacy of black raspberries on the histopathology of progressive cervical lesions present in the transformation zone.…”

Attenuation of multi-targeted proliferation-linked signaling by 3,3′-diindolylmethane (DIM): From bench to clinic

“…Additionally, the authors revealed that DIM inhibits the development of E6/E7 oncogene-induced cervical lesions and increased serum INF-γ indicating increased immune response in the DIM-fed animals. Furthermore, to define the extent and the most effective minimum dose of DIM administration to augment the efficacy of preventive and therapeutic HPV vaccines, these investigators utilizing the K14-HPV16 transgenic mouse model concluded 1000ppm of DIM as the minimum effective and viable dose for future human studies [143]. The urinary DIM concentrations following 1000ppm DIM dose compare favorably to DIM measured in women taking either 200 or 400 mg of DIM twice daily for 4 weeks as reported earlier [138].…”

Cellular, Molecular and Biological Insight into Chemopreventive and Therapeutic Potential of 3,3’-Diindolylmethane (DIM)

“…The efficacy of DIM in K14-HPV16 transgenic mouse model of cervical cancer have also been evaluated and reported wherein 2,000 ppm DIM given for 12 weeks either delayed or inhibited the progression from cervical dysplasia to cervical cancer (Sepkovic et al 2009). To seek an answer for the most effective minimum dose of DIM administration for future human studies to augment the efficacy of preventive and therapeutic HPV vaccines, the dose of 1000 ppm of DIM was extrapolated as the minimum effective and viable dose for future human studies (Sepkovic et al 2011). This 1000 ppm DIM dose compare favorably to DIM measured in women taking either 200 or 400 mg of DIM twice daily for 4 weeks as reported earlier (Sepkovic et al 2001).…”