Harnessing Redox Disruption to Treat Human Herpesvirus 8 (HHV-8) Related Malignancies

Abstract

Reprogrammed metabolism is regarded as a hallmark of cancer and offers a selective advantage to tumor cells during carcinogenesis. The redox equilibrium is necessary for growth, spread and the antioxidant pathways are boosted following Reactive Oxygen Species (ROS) production to prevent cell damage in tumor cells. Human herpesvirus 8 (HHV-8), the etiologic agent of Kaposi sarcoma KS and primary effusion lymphoma (PEL), is an oncogenic virus that disrupts cell survival-related molecular signaling pathways leading to immune host evasion, cells growths, angiogenesis and inflammatory tumor-environment. We recently reported that primaquine diphosphate causes cell death by apoptosis in HHV-8 infected PEL cell lines in vivo and exhibits therapeutic anti-tumor activity in mice models and advanced KS. Our findings also suggest that the primaquine-induced apoptosis in PEL cells is mostly influenced by ROS production and targeting the redox balance could be a new approach to treat HHV-8 related diseases. In this review, we summarized the knowledge about the influence of ROS in cancer development; more specifically, the proof of evidence from our work and from the literature that redox pathways are important for the development of HHV-8 pathologies.

Keywords: HHV-8; Kaposi sarcoma; metabolism; oncogenesis; oxidoreduction disruption; primary effusion lymphoma.

Figure 1

Schematic representation of the redox homeostasis in cancer cells. The redox balance is crucial for normal and cancer cells survival. In normal condition, an increase of ROS generation leads to the activation of different pathways involved in programmed cell death. In cancer cells, metabolism is disrupted and lead to an increase of ROS levels which can also activate different pro oncogenic pathways inducing cell survival and proliferation. To thwart the high rates of ROS, the oxidative stress can also stimulates the antioxidant system to reduce ROS levels and prevent the cells from cell death.

Figure 2

Schematic representation of primaquine action on KSHV-infected cells to induce apoptosis. Oxidative stress induced by the primaquine leads to an increase of ROS and decrease of the GSF. In response to the oxidative stress, the pro-apoptotic UPR pathway is activated and induced the up-regulation of the ATF3, CHAC-1 and OSGIN1 transcripts. Caspase-4 pathway could also be activated directly through the activation of the UPR pathway. The oxidative stress induced by primaquine could also inhibated the NFkB pathway, leading to the lifting of the negative retrocontrole on the expression of the caspase-3. Altogether, our result suggest that the primaquine could induced apoptosis on KSHV-infected cells by stimulating different pro-apoptotic pathways.