Antimicrobial sulfonamides clear latent Kaposi sarcoma herpesvirus infection and impair MDM2–p53 complex formation

Abstract

Kaposi Sarcoma Herpesvirus (KSHV), also known as Human Herpesvirus 8, is the causative agent of Kaposi sarcoma; this malignant angiosarcoma is usually treated with conventional anti-tumor agents, which can control disease evolution, but do not clear the latent KSHV episome that binds to cellular DNA. Some commercial antibacterial sulfonamides were tested for the ability to suppress latent KSHV. qPCR and cytofluorometry assays were used for detecting both viral DNA and the latency factor LANA in BC3 cells, respectively. The capacity of sulfonamides to impair MDM2-p53 complex formation was detected by an ELISA method. The analysis of variance was performed according to one-way ANOVA with Fisher as a post-hoc test. Here we show that sulfonamide antibiotics are able to suppress the KSHV latent state in permanently-infected BC3 lymphoma-cells and interfere with the formation of the MDM2-p53 complex, which KSHV seemingly needs to support latency and to trigger tumor cell transformation. These findings detected a new molecular target for the activity of sulfonamides and offer a new potential perspective for treating KSHV-induced lymphoproliferative diseases.

The Use of Antimalarial Drugs against Viral Infection

“…The results showed that the sulfadoxine-pyrimethamine combination combined with antiretroviral therapy significantly enhanced HIV replication in MT-2 cells, while it inhibited HIV replication in peripheral blood mononuclear cells [23]. Moreover, recent studies have demonstrated that sulfonamides can act on latent herpesviruses, such as EBV and Kaposi sarcoma herpesvirus (KSHV) [182,183]. Furthermore, a work conducted by Angius and colleagues reported that sulfonamide antibiotics suppressed the KSHV latent state in permanently infected lymphoma cells [183].…”

“…Moreover, recent studies have demonstrated that sulfonamides can act on latent herpesviruses, such as EBV and Kaposi sarcoma herpesvirus (KSHV) [182,183]. Furthermore, a work conducted by Angius and colleagues reported that sulfonamide antibiotics suppressed the KSHV latent state in permanently infected lymphoma cells [183]. This result suggested that sulfonamides might play a potential role in clearing KSHV-infected lymphoma cells.…”

“…Herpesviridae HSV-1 Quinine sulfate in vivo [68,69] EBV Artesunate in vitro [50] Sulfonamides in vitro [182] HCMV Artemisinin in vitro [16] Artesunate in vitro [10,11,16,17,[24][25][26][27][28][29][30][31][32][33][34] Arthemeter in vitro [61,62] HHV-6 Artesunate in vitro [51,53] HHV-6B Artesunate in vitro [52] KSHV Doxycycline in vitro [183] HSE Artemisinin in vivo (mouse) [35] Dihydroartemisinin in vitro [16] KSHV Sulfonamides in vitro [183] RCMV Artesunate in vivo (rat) [11] Polyomaviridae BKPyV Artesunate in vitro [55] JCPyV Artesunate in vitro [54] Mefloquine in vitro [71] Hepadnaviridae HBV Artemisinin, artesunate in vitro [17] Papillomaviridae HPV Artemisinin in vitro [18] Dihydroartemisinin in vivo (dog) [19] Doxycycline in vitro [177]…”

Human Herpesvirus 8 and Host-Cell Interaction: Long-Lasting Physiological Modifications, Inflammation and Related Chronic Diseases

“…In particular, Paul et al [22] demonstrated that a known sulfone drug, namely nimesulide, can affect HHV8 latency by interacting with its binding to cell DNA. In addition, some sulfonamide drugs have recently been shown to be able to interfere with the binding of LANA to the cellular DNA [23]. It is worth noting that several other DNA (e.g., Adenoviruses and Herpesviruses) and RNA (e.g., Rubella, Dengue virus, Enteroviruses, Hepatitis C virus and HIV) viruses were found to be able to affect the host's metabolism favouring not only the onset of tumours but also some other chronic diseases, namely metabolic syndrome and diabetes [4,[24][25][26][27][28][29].…”

p53 Controls Murine Gammaherpesvirus Latency and Prevents Infection-AssociatedIgH/c-MycTranslocations

“…Whether GHVs inhibit p53 as a matter of course during latency has become controversial.Although KSHV LANA was demonstrated to potently inhibit p53(26), several subsequent studies have challenged this original finding. PEL cells harboring latent KSHV and expressing high levels of LANA, as well as other latency-associated transcripts, remain sensitive to p53 agonists, responding to treatment with potent p53 stabilization, p53-related gene expression, and cell death(28,71,72). In contrast, KSHV-infected cells are resistant to p53-mediated death during lytic replication(73).…”