title: Comparative analysis of ER stress response into HIV protease inhibitors: lopinavir but not darunavir induces potent ER stress response via ROS/JNK pathway.
abstract: HIV protease inhibitor (PI)-induced ER stress has been associated with adverse effects. Although it is a serious clinical problem for HIV/AIDS patients, comparative analyses of ER stress induction by clinically used PIs have rarely been done. Especially, there is no report on the differential ER stress response between lopinavir (LPV) and darunavir (DRV), although these PIs are the most clinically used PIs. We show here that LPV induces the most potent CHOP expression, ER stress marker, among the 9 Food and Drug Administration (FDA)-approved PIs in human peripheral blood mononuclear cells, several human epithelial cells, and mouse embryonic fibroblasts. LPV induced the most potent ROS production and JNK activation in 9 PIs. A comparison among the most clinically used PIs, ritonavir (RTV), LPV, and DRV, revealed that LPV potently and RTV moderately but not DRV induced ER stress via ROS-dependent JNK activation rather than proteasome inhibition. Finally, we analyzed ER stress induction in tissues of mice intraperitoneally injected with RTV, LPV, and DRV. RTV and LPV but not DRV showed ER stress induction in several mice tissues. In conclusion, we first identify LPV as the most potent ER stress inducing PI among 9 FDA-approved PIs in human cells, and although clinical verification is necessary, we show here that DRV has the advantage of less ROS and ER stress induction potential compared with LPV in vitro and in vivo.
authors: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan.
authors: Manabu
authors: M
authors: Taura
authors: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan.
authors: Ryusho
authors: R
authors: Kariya
authors: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan.
authors: Eriko
authors: E
authors: Kudo
authors: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan.
authors: Hiroki
authors: H
authors: Goto
authors: Iwawaki Laboratory, Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi 371-8511, Japan.
authors: Takao
authors: T
authors: Iwawaki
authors: Department of Infectious Diseases and Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Masayuki
authors: M
authors: Amano
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors: Mary Ann
authors: MA
authors: Suico
authors: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors: Hirofumi
authors: H
authors: Kai
authors: Department of Infectious Diseases and Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Hiroaki
authors: H
authors: Mitsuya
authors: Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan. Electronic address: okadas@kumamoto-u.ac.jp.
authors: Seiji
authors: S
authors: Okada
mesh_terms: D000818:Animals; D017209:Apoptosis; D000069454:Darunavir; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D057809:HEK293 Cells; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D061466:Lopinavir / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D061466:Lopinavir; D048031:JNK Mitogen-Activated Protein Kinases; D000069454:Darunavir
keywords: AIDS; APV; ARE; ATV; Amprenavir; Atazanavir; CHOP; Combination antiretroviral therapy; DRV; Darunavir; ER stress; FDA; Food and Drug Administration; HIV protease inhibitor; IDV; Indinavir; JNK; LDH; LPV; Lopinavir; N-acetyl-L-cysteine; NAC; NFV; Nelfinavir; PBMC; PI; PRI; Peripheral blood mononuclear cells; Propidium iodide; Protease inhibitor; ROS; RTV; Ritonavir; SQV; Saquinavir; TPV; Tiprenavir; antioxidant response; cART; lactate dehydrogenase