Molecular Mechanisms of HIV Protease Inhibitors Against HPV-Associated Cervical Cancer: Restoration of TP53 Tumour Suppressor Activities

Abstract

Cervical cancer is a Human Papilloma virus-related disease, which is on the rise in a number of countries, globally. Two essential oncogenes, E6 and E7, drive cell transformation and cancer development. These two oncoproteins target two of the most important tumour suppressors, p53 and pRB, for degradation through the ubiquitin ligase pathway, thus, blocking apoptosis activation and deregulation of cell cycle. This pathway can be exploited for anticancer therapeutic interventions, and Human Immunodeficiency Virus Protease Inhibitors (HIV-PIs) have attracted a lot of attention for this anticancer drug development. HIV-PIs have proven effective in treating HPV-positive cervical cancers and shown to restore impaired or deregulated p53 in HPV-associated cervical cancers by inhibiting the 26S proteasome. This review will evaluate the role players, such as HPV oncoproteins involved cervical cancer development and how they are targeted in HIV protease inhibitors-induced p53 restoration in cervical cancer. This review also covers the therapeutic potential of HIV protease inhibitors and molecular mechanisms behind the HIV protease inhibitors-induced p53-dependent anticancer activities against cervical cancer.

Advances in HPV‐associated tumor management: Therapeutic strategies and emerging insights

“…HIV protease inhibitors (HIV‐PIs) exhibit inhibitory effects on tumor cell growth, invasion, and angiogenesis. They also induce cell apoptosis, block the cell cycle, and have shown promise in treating HPV‐positive CC by restoring damaged or dysregulated p26 in CC through the inhibition of the 53 S proteasome 88 …”

A systematic review on the molecular and clinical association between Human Papillomavirus and Human Immunodeficiency Virus co‐infection in Head, Neck and Oral squamous cell carcinoma

“…Cancer is a non-transmittable disease, but it can be induced by oncogenic viruses, which have the potential to activate protooncogenes. 85 As we have already discussed, that infection caused due to HPV induces cancer in some patients and can also infect patients with immune deficiencies, such as HIV/AIDS patients. 18 The poor management of HPV-associated risk or HPV infection in the oral region generally leads to the development of cancer in the oral region of the human body.…”

“…cancer and HPV infection, various types of cancer are prompted to arise. 85 Meanwhile, HPV vaccination was developed in 2006, which has great potential in preventing HPV infection and tumour development. Further, it is highly suggested for children, adolescents, and young adults with or without HIV/AIDS.…”

“…91 HIV protease inhibitors are proposed to restore the activity of tumour suppressor genes p53 in HPV-associated cancer and induce the p53-dependent antitumour activity. 85…”

“…These proteins turn off normal cellular apoptosis by inhibiting tumour necrosis factors related to apoptosis-inducing ligands (TRAIL), P53, and pRb, respectively. 85 Clinical studies with HIV and HPV-related co-infection cases from various countries showed contrasting results. An investigation from a cohort study revealed that HIV does not interfere with HPVpositive or HPV-associated cancer.…”