Catalpol‐Induced AMPK Activation Alleviates Cisplatin‐Induced Nephrotoxicity through the Mitochondrial‐Dependent Pathway without Compromising Its Anticancer Properties

Abstract

Nephrotoxicity is a common complication of cisplatin chemotherapy and, thus, limits the clinical application of cisplatin. In this work, the effects of catalpol (CAT), a bioactive ingredient extracted from Rehmannia glutinosa, on cisplatin-induced nephrotoxicity and antitumor efficacy were comprehensively investigated. Specifically, the protective effect of CAT on cisplatin-induced injury was explored in mice and HK-2 cells. In vivo, CAT administration strikingly suppressed cisplatin-induced renal dysfunction, morphology damage, apoptosis, and inflammation. In vitro, CAT induced activation of adenosine 5 ′ -monophosphate- (AMP-) activated protein kinase (AMPK), improved mitochondrial function, and decreased generation of cellular reactive oxygen species (ROS), leading to a reduction in inflammation and apoptosis, which ultimately protected from cisplatin-induced injury. However, the beneficial effects of CAT were mostly blocked by coincubation with compound C. Furthermore, molecular docking results indicated that CAT had a higher affinity for AMPK than other AMPK activators such as danthron, phenformin, and metformin. Importantly, CAT possessed the ability to reverse drug resistance without compromising the antitumor properties of cisplatin. These findings suggest that CAT exerts positive effects against cisplatin-induced renal injury through reversing drug resistance via the mitochondrial-dependent pathway without affecting the anticancer activity of cisplatin.

Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats

“…In the current work, cisplatin caused downregulation of ovarian AMPK mRNA expression compared to the control group. Cisplatin has been reported to cause renal injury through the downregulation of AMPK expression [86,87]. In contrast, melatonin co-administration with cisplatin increased the expression of AMPK mRNA in the ovarian tissues.…”

Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential

“…Additionally, it has been reported that inhibition of autophagy accelerated ROS production and apoptosis induced by CP, while its activation reversed these effects ( Zhao et al, 2017 ). Moreover, activation of AMPK attenuated CP-induced AKI by improving mitochondrial function and suppressing the formation of ROS and apoptosis responses caused by CP, all of which effects were abolished upon AMPK inhibition ( Zhang J. et al, 2021 ). Furthermore, restoration of autophagy flux by polydatin ameliorated CP-induced oxidative stress, inflammation, and cell apoptosis, thereby alleviating CP-induced AKI ( Li et al, 2022c ).…”

Roles of Reactive Oxygen Species and Autophagy in the Pathogenesis of Cisplatin-Induced Acute Kidney Injury

“…In particular, the dysfunction of the mitochondrial respiratory chain results in the further excess production of ROS that contributes to severe kidney injury [20]. Consequently, the mitochondrial dysfunction induced by the treatment with cisplatin could be considered as due to increased levels of ROS resulting in various cellular apoptosis including kidney cells [2,21]. Increased levels of ROS can also contribute to the tubular cell apoptosis in kidney, thereby causing more severe kidney injury during AKI [22].…”