Primaquine as a Candidate for HHV-8-Associated Primary Effusion Lymphoma and Kaposi’s Sarcoma Treatment

Cancers

Emmanuel Laplantine¹  Nicolas Dupin²  Philippe Grange²  Ousmane Faye³  Nathalie Désiré⁴  Adélie Gothland⁵  Sophie Sayon⁵  Vincent Calvez⁵  Laurianne Beauvais Remigereau⁵  Aude Jary⁵  Valentin Leducq⁵  Anne-Geneviève Marcelin⁵  Almoustapha Issiaka Maiga⁶ 

[1] Center for Immunology and Microbial Infections—CIMI-Paris, Sorbonne Université, INSERM, CNRS, 75013 Paris, France;Cutaneous Biology Lab, INSERM U1016, UMR8104, Institut Cochin, Université de Paris, 24 Rue du Faubourg St Jacques, 75014 Paris, France;Département de Dermatologie, Faculté de Médecine et de Pharmacie, Université de Bamako, Bamako BP 1805, Mali;Institut Pierre Louis d’Epidémiologie et de Santé Publique, INSERM, Assistance Publique—Hôpitaux de Paris, Sorbonne Université, 75012 Paris, France;Service de Virologie, Hôpital Pitié Salpêtrière, Institut Pierre Louis d’Epidémiologie et de Santé Publique (iPLESP), INSERM UMR_1136, Sorbonne Université, 75013 Paris, France;Unité d’Epidémiologie Moléculaire de la Résistance du VIH aux ARV, SEREFO, FMOS, University of Sciences, Techniques and Technologies of Bamako, Bamako BP 1805, Mali;

关键词: human herpesvirus 8;    Kaposi’s sarcoma;    primary effusion lymphoma;    primaquine diphosphate;    oxidative stress;    apoptosis;   

DOI  :  10.3390/cancers14030543

来源: DOAJ

【 摘 要 】

Human Herpesvirus 8 (HHV-8) is associated with three main severe orphan malignancies, Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD), and primary effusion lymphoma (PEL), which present few therapeutic options. We identified the antimalarial primaquine diphosphate (PQ) as a promising therapeutic candidate for HHV-8-associated PEL and KS. Indeed, PQ strongly reduced cell viability through caspase-dependent apoptosis, specifically in HHV-8-infected PEL cells. Reactive oxygen species (ROS)- and endoplasmic reticulum (ER) stress-mediated apoptosis signaling pathways were found to be part of the in vitro cytotoxic effect of PQ. Moreover, PQ treatment had a clinically positive effect in a nonobese diabetic (NOD)/SCID xenograft PEL mouse model, showing a reduction in tumor growth and an improvement in survival. Finally, an exploratory proof-of-concept clinical trial in four patients harboring severe KS was conducted, with the main objectives to assess the efficacy, the safety, and the tolerability of PQ, and which demonstrated a positive efficacy on Kaposi’s sarcoma-related lesions and lymphedema.

【 授权许可】

Unknown