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HIV protease inhibitors elicit volume-sensitive Cl current in cardiac myocytes via mitochondrial ROS
Wu Deng Jun Yin Clive M. Baumgarten 《Journal of molecular and cellular cardiology》2010,49(5):746-752
HIV protease inhibitors (HIV PI) reduce morbidity and mortality of HIV infection but cause multiple untoward effects. Because certain HIV PI evoke production of reactive oxygen species (ROS) and volume-sensitive Cl− current (ICl,swell) is activated by ROS, we tested whether HIV PI stimulate ICl,swell in ventricular myocytes. Ritonavir and lopinavir elicited outwardly rectifying Cl− currents under isosmotic conditions that were abolished by the selective ICl,swell-blocker DCPIB. In contrast, amprenavir, nelfinavir, and raltegravir, an integrase inhibitor, did not modulate ICl,swell acutely. Ritonavir also reduced action potential duration, but amprenavir did not. ICl,swell activation was attributed to ROS because ebselen, an H2O2 scavenger, suppressed ritonavir- and lopinavir-induced ICl,swell. Major ROS sources in cardiomyocytes are sarcolemmal NADPH oxidase and mitochondria. The specific NADPH oxidase inhibitor apocynin failed to block ritonavir- or lopinavir-induced currents, although it blocks ICl,swell elicited by osmotic swelling or stretch. In contrast, rotenone, a mitochondrial e− transport inhibitor, suppressed both ritonavir- and lopinavir-induced ICl,swell. ROS production was measured in HL-1 cardiomyocytes with C-H2DCFDA-AM and mitochondrial membrane potential (ΔΨm) with JC-1. Flow cytometry confirmed that ritonavir and lopinavir but not amprenavir, nelfinavir, or raltegravir augmented ROS production, and HIV PI-induced ROS production was suppressed by rotenone but not NADPH oxidase blockade. Moreover, ritonavir, but not amprenavir, depolarized ΔΨm. These data suggest ritonavir and lopinavir activated ICl,swell via mitochondrial ROS production that was independent of NADPH oxidase. ROS-dependent modulation of ICl,swell and other ion channels by HIV PI may contribute to some of their actions in heart and perhaps other tissues. 相似文献
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Svedhem V Lindkvist A Bergroth T Knut L Sönnerborg A 《Journal of medical virology》2005,76(4):447-451
The aim of the study was to describe the pattern of resistance mutations in human immunodeficiency virus type 1 (HIV‐1) infected patients experiencing their first protease inhibitor (PI) failure on nelfinavir (NFV)‐containing therapy. Earlier PI‐naïve patients (n = 172) with NFV‐containing therapy were therefore retrospectively studied. Plasma HIV RNA from 43 failing patients was sequenced. In addition, virus from the baseline was sequenced in 29 patients. Failure was defined as two consecutive measurements of viral load of >50 copies/ml after 6 months treatment. Subtyping was done in most patients (n = 118). At baseline, the V82A mutation was found in four PI‐naïve patients of whom two failed therapy exhibiting this mutation. At therapy failure, 17 of the 43 (40%) patients had primary PI mutations. In nine subjects, RTI‐mutations only were found and 17 patients had a wild‐type virus. Patients with primary PI and/or RTI mutations had a higher viral load at failure than those who failed with wild‐type virus. A surprisingly diverse pattern of primary PI mutations was seen: M46I (n = 7), D30N (n = 6), L90M (n = 5), and V82A (n = 4). Four patients exhibited more than one primary PI mutation. PI‐naïve patients in Sweden may harbor PI‐resistant virus and resistance testing should be considered before treatment. Patients who fail NFV may develop the M46I mutation, which has been related earlier to mainly other PI. The diverse pattern of the evolved PI‐mutations and the relative low occurrence of the D30N mutation in the material was unexpected and did not seem to be related to the viral subtype. J. Med. Virol. 76:447–451, 2005. © 2005 Wiley‐Liss, Inc. 相似文献
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Hee-Yeon Cho Simmy Thomas Encouse B. Golden Kevin J. Gaffney Florence M. Hofman Thomas C. Chen Stan G. Louie Nicos A. Petasis Axel H. Schönthal 《Cancer letters》2009
Moderate activity of the endoplasmic reticulum (ER) stress response system exerts anti-apoptotic function and supports tumor cell survival and chemoresistance, whereas its more severe aggravation may exceed the protective capacity of this system and turn on its pro-apoptotic module. In this study, we investigated whether the combination of two pharmacologic agents with known ability to trigger ER stress via different mechanisms would synergize and lead to enhanced tumor cell death. We combined the HIV protease inhibitor nelfinavir (Viracept®) and the cyclooxygenase 2 (COX-2) inhibitor celecoxib (Celebrex®) and investigated their combined effect on ER stress and on the viability of breast cancer cells. We found that this drug combination aggravated ER stress and caused pronounced toxicity in human breast cancer cell lines, inclusive of variants that were highly resistant to other therapeutic treatments, such as doxorubicin, paclitaxel, or trastuzumab. The anti-tumor effects of celecoxib were mimicked at increased potency by its non-coxib analog, 2,5-dimethyl-celecoxib (DMC), but were substantially weaker in the case of unmethylated-celecoxib (UMC), a derivative with superior COX-2 inhibitory efficacy. We conclude that the anti-tumor effects of nelfinavir can be enhanced by celecoxib analogs in a COX-2 independent fashion via the aggravation of ER stress, and such drug combinations should be considered as a beneficial adjunct to the treatment of drug-resistant breast cancers. 相似文献
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