Abstract
Cis-dichlorodiammineplatinum II (CDDP) is a chemotherapeutic agent that induces nephrotoxicity by different mechanisms, including oxidative stress, mitochondrial dysfunction, autophagy, and endoplasmic reticulum stress. This study aimed to evaluate if the protective effects of the antioxidant alpha-mangostin (αM) in CDDP-induced damage in proximal tubule Lilly laboratory culture porcine kidney (LLC-PK1) cells, are related to mitochondrial function preservation. It was found that αM co-incubation prevented CDDP-induced cell death. Furthermore, αM prevented the CDDP-induced decrease in cell respiratory states, in the maximum capacity of the electron transfer system (E) and in the respiration associated to oxidative phosphorylation (OXPHOS). CDDP also decreased the protein levels of voltage dependence anion channel (VDAC) and mitochondrial complex subunits, which together with the reduction in E, the mitofusin 2 decrease and the mitochondrial network fragmentation observed by MitoTracker Green, suggest the mitochondrial morphology alteration and the decrease in mitochondrial mass induced by CDDP. CDDP also induced the reduction in mitochondrial biogenesis observed by transcription factor A, mitochondria (TFAM) decreased protein-level and the increase in mitophagy. All these changes were prevented by αM. Taken together, our results imply that αM’s protective effects in CDDP-induced toxicity in LLC-PK1 cells are associated to mitochondrial function preservation.
Highlights
Cis-dichlorodiammineplatinum II (CDDP) is a platinum compound frequently used in many types of cancers [1,2]
Cell Death (Figure 1A) and it was observed that at 30 M CDDP, reduced approximately 50% of cell viability, as LLC-PK1 cells were incubated with various CDDP concentrations: 5, 10, 20, 30, and 40 μM
To determine if the observed reduction in mitochondrial mass was related to alterations in mitochondrial biogenesis, we evaluated the levels of mitochondrial biogenesis proteins PCG-1α, nuclear respiratory factor 1 (NRF1), and TFAM
Summary
Cis-dichlorodiammineplatinum II (CDDP) is a platinum compound frequently used in many types of cancers [1,2]. The main side-effect of CDDP is its nephrotoxicity, especially in proximal tubule epithelial cells. It is estimated that 20 to 30% of patients treated with CDDP developed transient episodes of acute kidney injury, which can progress to chronic kidney disease, depending on the dose and individual pharmacokinetics [2]. The CDDP-toxicity mechanisms involve DNA damage, oxidative stress, mitochondrial damage, endoplasmic reticulum (ER) stress, autophagy, and apoptotic cell death [3,4]. The use of biomolecules with antioxidant activity has been widely studied to mitigate the nephrotoxic effects induced by CDDP [5]. Alpha-mangostin (αM), a bioactive compound with direct antioxidant properties that can be extracted from the Garcinia mangostana tree, has been broadly used in Antioxidants 2019, 8, 133; doi:10.3390/antiox8050133 www.mdpi.com/journal/antioxidants
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