Biological activities of ficus carica latex for potential therapeutics in human papillomavirus (HPV) related cervical cancers

Cancer is a major public health concern and is one of the leading causes of death worldwide. Cervical cancer is one of the most common types of cancer, affecting women on a global scale. Infection caused by high-risk human papillomaviruses (HPVs), especially type 16 and 18 are implicated in the aetiology of most cervical cancers. Coupled with their involvement in cancer, these viruses can cause life-long debilitating diseases that may be accompanied by a significant negative impact on quality of life. High- risk HPV infections interfere with the molecular pathways that are responsible for regulating epithelial differentiation as well as cell proliferation. HPV onco-proteins E6 and E7 contribute towards cellular changes in HPV infected cells. These facilitate the persistence of infection that might allow the progression of the lesions towards cancer. E6 interacts physically with tumour suppressor protein p53 and prevents its function; this activity will ultimately impede apoptosis. On the other hand, E7 binds to retinoblastoma (Rb) protein and prevents the interaction of Rb with its natural target, namely transcription factor E2F. Consequently the checkpoint that controls G1/S transition becomes distorted, causing uncontrolled proliferative lesions. Once proliferative lesions persist they can progress to high-grade ones and become an invasive form of cervical cancer . It has been demonstrated that the presence of even minimal amounts of HPV DNA are associated with an increased risk in the development of cervical cancer. Given the importance of cervical cancer, to date, there has been no satisfactory medical treatment for human papillomavirus related cervical cancer as most of the developed treatments (e.g., surgical excision, chemotherapy, and cryotherapy) are eventually accompanied by excessive tissue injury. Therefore, there is a continuing demand for development of new strategies for treatment, which avoids tissue injury. Herbal medicinal and biological studies have revealed that public interest in utilising traditional remedies has greatly increased. Among various medically relevant plants, the xiii fig latex (Ficus carica), when applied to low risk human papillomavirus (HPV) related skin warts and bovine papillomavirus (BPV) related warts, has shown potential as a possible cure for the virus without inevitable tissue injury and remedial complications. Fig latex also reportedly offers various therapeutic effects such as anti-Herpes Simplex Virus (HSV)-1, anti-bacterial activity and anthelmintic. As a consequence we investigated the biological activity of the Ficus carica latex on high risk HPV related cervical cancer. Herein, we show that Ficus carica latex effectively inhibits growth of HPV positive cervical cancer cells (CaSki and HeLa), without a cytotoxic effect on HPV and cancer-free human immortalised keratinocyte (HaCaT) cell line. The latex presents anti-cancer effects by various mechanisms, including induction of apoptosis and inhibition of cell transformation; colony formation, cell proliferation, migration and invasion. In addition to its potent anti-cancer effects, the results obtained indicate that Fig latex has profound influence on the deregulation of HPV oncoproteins (E6 and E7) and HPV diagnostic marker protein (p16) and initiates the reactivation of Rb and p53 tumor suppressor proteins. These findings provide insight into new therapeutic avenues against HPV- associated cervical cancers.