Poly(ADP-Ribose) Polymerase Inhibition as a Promising Approach for Hepatocellular Carcinoma Therapy

Abstract

Primary liver cancer is the sixth most common cancer in men and seventh in women, with hepatocellular carcinoma (HCC) being the most common form (75-85% of primary liver cancer cases) and the most frequent etiology being viral infections (HBV and HCV). In 2020, mortality represented 92% of the incidence-830,180 deaths for 905,677 new cases. Few treatment options exist for advanced or terminal-stage HCC, which will receive systemic therapy or palliative care. Although radiotherapy is used in the treatment of many cancers, it is currently not the treatment of choice for HCC, except in the palliative setting. However, as radiosensitizing drugs, such as inhibitors of DNA repair enzymes, could potentiate the effects of RT in HCC by exploiting the modulation of DNA repair processes found in this tumour type, RT and such drugs could provide a treatment option for HCC. In this review, we provide an overview of PARP1 involvement in DNA damage repair pathway and discuss its potential implication in HCC. In addition, the use of PARP inhibitors and PARP decoys is described for the treatment of HCC and, in particular, in HBV-related HCC.

Keywords: hepatitis B virus (HBV) X protein; hepatocellular carcinoma (HCC); liver cancer; poly(ADP)ribose polymerases (PARP).

Figure 1

Synthetic lethality of PARP inhibitors in HBV-infected cells. It has been hypothesized that in a patient infected with HBV treated with PARP inhibitors, SSBs generated either intrinsically by oxidative stress or extrinsically by chemotherapy or radiotherapy remain unrepaired and are converted to DSBs. The impact of the degradation of the Smc5/6 complex by HBx on the HR pathway would result in the persistence of these DSBs and cell death.