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Oncology
Cisplatin, a potent chemotherapeutic agent, is marred by severe nephrotoxicity that is governed by mechanisms involving oxidative stress, inflammation, and apoptosis pathways. The transcription factor Nrf2, pivotal in cellular defense against oxidative stress and inflammation, is the master regulator of the antioxidant response, upregulating antioxidants and cytoprotective genes under oxidative stress.
- oxidative stress
- reactive oxygen species
- Nrf2
- chemotherapy
- kidney injury
1. Chemotherapy-Induced Kidney Injury
The development of nephrotoxicity is a common side effect of several chemotherapeutic agents causing adverse structural as well as functional changes in the kidney contributing to the pathology of kidney disease. The drugs most associated with chemotherapy-induced renal implications include cisplatin [27,28,29], ifosfamide [30,31,32,33], methotrexate [34,35], cyclophosphamide [11,36], Bevacizumab [37], streptozotocin [38], and gemcitabine [39].
One of the most used chemotherapy drugs is cisplatin (cis-diamminedichloroplatinum II), a platinum-containing antineoplastic drug extensively used to treat a variety of cancers and notorious for its toxic effects on the kidney. Being one of the most potent and effective chemotherapies, cisplatin is used to treat testicular, cervical, breast, small cell lung, and bladder cancers [40,41,42,43]. It is broadly accepted that cisplatin exerts its damaging effects by causing intra or interstrand crosslinks with purine bases on DNA which impairs DNA repair pathways causing cell cycle arrest and ultimately cell death [44,45]. Regardless of the effectiveness of cisplatin in sensitizing a plethora of cancers, its usage is rationed due to its adverse nature causing ototoxicity [46,47,48], nephrotoxicity [45,49], and neurotoxicity [50,51]. Cisplatin enters the renal tubular cells through its uptake transporters (OCT2) and (CTR1) and forms reactive metabolites that cause DNA damage, and oxidative stress, and disrupt cellular function [52,53]. Cisplatin also affects the resorption of electrolytes by tubular cells leading to electrolyte imbalances, an increase in serum creatinine, fluid retention, increased intratubular pressure, and reduced urine output, all of which lead to renal functional decline and are classic characteristics of Acute Kidney Injury (AKI) [52,54]. Higher cumulative doses of cisplatin and recurrent episodes of AKI can increase the risk of developing CKD [55]. Risk factors for cisplatin include pre-existing renal conditions, old age, previous dosing with cisplatin, and genetic factors that affect the metabolism of the drug in the kidney and its elimination [56].
Methotrexate (MTX) is an antifolate therapy, most commonly used in the treatment of rheumatoid arthritis (RA) [57], psoriasis [58], inflammatory bowel disease, and a variety of cancers, including lung, breast, and leukemia. The primary mechanism of action involves the inhibition of dihydrofolate reductase (DHFR) which is involved in purine and pyrimidine synthesis [57], the building blocks for DNA and RNA. The usage of methotrexate is limited due to nephrotoxicity with high doses of MTX (>500 mg/m2) inducing AKI through a mechanism involving oxidative stress and inflammation leading to apoptosis [59,60,61].
Cyclophosphamide, an antineoplastic agent with a cytotoxic and immunosuppressive profile is often used to treat autoimmune disease as well as systemic lupus [62]. It is also used to treat lymphomas, leukemia, and certain type of solid tumors. Cyclophosphamide is converted to its active metabolites by cytochrome p450s in the liver and primarily causes nephrotoxicity due to its metabolite, phosphoramide mustard, that produces the inter- and intrastrand DNA crosslinks [63]. Although considered an effective anticancer agent, cyclophosphamide can have detrimental effects on the kidneys including hemorrhagic cystitis, tubular toxicity, and glomerular toxicity [11].
Ifosamide (IFO), an analog of cyclophosphamide, is also an alkylating agent used to treat soft tissue sarcomas, testicular cancers, and lymphomas, and can be nephrotoxic at high doses [64,65]. IFO requires metabolic activation by cytochrome p450s to be converted to a 4-hydroxy form which in turn spontaneously releases the active form, isophosphoramide mustard [66]. Other parallel pathways for IFO metabolism include its inactive metabolites (2-dechloroethylifosfamide and 3-dechloroethylifosfamide) [66]. IFO can cause renal tubular dysfunction causing hypokalemia, hypophosphatemia, and several other electrolyte imbalances [67]. Furthermore, it can manifest as urinary excretion of glucose, bicarbonate, and amino acids [67]. Additionally, it can promote tubular interstitial injury that can present as AKI or in some cases progressive CKD [68]. IFO and its metabolites can also cause inflammation of the bladder leading to hemorrhagic cystitis which can result in bladder pain, bloody urine, and urinary frequency [69].
Doxorubicin, an anthracycline drug first extracted from Streptomyces peucetius var. caesius in the 1970s is used in breast cancer, lymphomas and lung cancer [70]. While treatment with doxorubicin although primarily affects the cardiovascular system, there are renal implications including glomerular and tubular damage, nephrotoxicity, and AKI [71]. Although the primary mechanism of doxorubicin-induced nephrotoxicity is not fully understood, several studies have elucidated a role for oxidative stress, inflammation, and direct renal toxicity with damage to the glomerular structure resulting in proteinuria, impaired renal function, and AKI [70,71]. It has been noted that patients receiving higher cumulative doses of doxorubicin or those with pre-existing renal conditions may be at a higher risk of developing renal injury [72].
Kidney toxicity caused by anticancer, chemotherapeutic agents is often associated with higher doses or prolonged drug exposure. Additional factors that affect the presentation and degree of kidney injury include age, sex, and comorbidities.
Chemotherapy-induced kidney injury can occur through direct mechanisms whereby drugs directly damage renal cells in the tubules and glomeruli (e.g., Cisplatin, methotrexate, cyclophosphamide, and ifosfamide). Several chemotherapy drugs can also induce oxidative stress and trigger an inflammatory response resulting in kidney injury. Impaired blood flow and oxygen delivery to renal tissue can lead to renal tubulointerstitial hypoxia and vascular damage which can disrupt the normal functioning of the kidney, thus contributing to renal impairment [73,74]. Immune checkpoint inhibitors (ICIs) used in the management of many advanced cancers can result in acute interstitial nephritis [75]. In addition, chemotherapy-induced renal dysfunction has been linked to mitochondrial structural and functional alterations that can present as dysregulation of the mitochondrial electron transport chain complexes, altered mitochondria membrane potential as well as reduced ATP levels and increased generation of reactive oxygen species (ROS) [16,53,76]. Increased levels of ROS generated from oxidative phosphorylation and/or NAPDPH oxidases can impair renal homeostasis and function, leading to inflammation, tissue damage, and fibrosis [77]. Endogenous cellular antioxidant systems effectively alleviate these ROS increases, thus maintaining the redox status (balance between pro-oxidants and antioxidants) of cellular systems.
2. Role of Nrf2 in Autophagy and Cisplatin-Induced Kidney Injury
Nrf2 exerts its influence on autophagy through a range of mechanisms, encompassing the transcriptional regulation of autophagy-promoting genes [116], facilitation of lysosomal biogenesis to ensure efficient autophagosome degradation [117], and orchestration of damaged and dysfunctional mitochondrial removal via mitophagy [118]. The activation of Nrf2 has been shown to upregulate several autophagy-related genes including ULK1, SQSTM1, ATG2B, ATG4D, and ATG5 [116]. Conversely, inhibiting Nrf2 has been associated with reduced expression of autophagy genes [119]. Notably, the disruption of KEAP1-mediated Nrf2 degradation, achieved through the sequestration of Keap1 by p62 into autophagosomes, has also been identified as a means of activating the Nrf2 transcriptional pathway [120]. Moreover, Nrf2 plays a pivotal role in the activation of TFEB/TFE3 [transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)], the master regulator of lysosomal biogenesis [117]. Recent research by Ong et al. found that Keap1 deficiency induced Nrf2 activation, leading to postdevelopmental lethality characterized by liver lysosome accumulation [117]. This study further elucidated that the loss of Keap1 precipitated aberrant TFEB/TFE3-dependent lysosomal biogenesis [117]. Nrf2 activation has also been implicated in the initiation of mitophagy, coupled with the promotion of mitochondrial biogenesis, and is aligned with the involvement of the mitophagic/autophagic adapter protein sequestosome-1 (SQSTM1/p62), which is a downstream transcriptional target of Nrf2 [118,121].
Autophagy is upregulated in cisplatin-induced acute kidney injury (AKI), leading to a noticeable elevation in p62 levels within renal tissues. Furthermore, the presence of p62 is essential for initiating the autophagic response and facilitating aggresome formation in the context of AKI [122]. In a murine model of cisplatin-induced AKI, a heightened abundance of autophagosomes was observed within the kidney cortex postcisplatin treatment [122]. Notably, the expression of LC3II, a direct marker for mature autophagosomes, exhibited a substantial increase following cisplatin administration, concomitant with elevated levels of Atg5, Atg7, and Becn1—key regulators of autophagosome formation [122]. In a separate study, mice with autophagy deficiency specifically in proximal tubules displayed exacerbated pathology in cisplatin-induced AKI compared to their WT counterparts [123]. This was evidenced by alterations in kidney function, heightened DNA damage levels, intensified p53 activation, increased apoptosis, augmented protein aggregates, and discernible changes in renal morphology [123]. Thus, the multifaceted role of Nrf2 in autophagy encompasses the mitigation of oxidative stress, attenuation of inflammation, and active modulation of the autophagic and mitophagic processes.
3. Redox Based Interventions for Nrf2 Modulation in Cisplatin-Induced Kidney Injury
The complex pathology of cisplatin-induced kidney injury and the persistent nature of cisplatin-induced renal side effects have consistently warranted the need for easily implementable therapeutic interventions and as such numerous redox-based approaches and studies in preclinical models have been implemented to demonstrate the beneficial effects of Nrf2 activation.
Pharmacological activation of Nrf2 has been investigated preclinically using small molecules activators including sulforaphane [124], dimethyl fumarate [125], and bardoxolone methyl (CDDO-Me) [126] that promote the nuclear translocation of Nrf2 thereby enhancing the expression of the downstream cytoprotective genes thus protecting against renal damage. In a study conducted be Mohammad et al. in 2022, sulforaphane was shown to improve mitochondrial function significantly. Also, it alleviated age-related kidney injury by increasing cortical Nrf2 expression and decreasing the protein expression of the Nrf2 repressor, Keap1 [124]. Another Nrf2 activator, dimethyl fumarate (DMF) is an approved therapeutic for multiple sclerosis [127] and has been shown to ameliorate cisplatin-induced renal tubular injury via increasing the expression of NQO1 and the suppression of inflammatory cytokines including TNF-α and IL-6 thereby reducing the consequent tubulointerstitial fibrosis [125]. The study showed that Wistar rats treated with 7500 ppm (parts per million) DMF in their diet for 5 weeks demonstrated an inhibition of cisplatin-induced outer medullary necrosis and degeneration as well as inhibited interstitial mononuclear cell infiltration [125] suggesting that treatment with an Nrf2 activator mitigates cisplatin-induced renal injury via an antioxidant-based mechanism that involves NQO1. CDDO-Me, a semisynthetic triterpenoid and a potent activator of the Nrf2 pathway, has also been shown to upregulate the antioxidant response and suppress proinflammatory signaling to reduce oxidative stress levels and inflammation in an in vitro model of cisplatin-induced cellular senescence in human proximal tubular cells [126]. Furthermore, it has also been shown to increase the expression of other redox-based, downstream effectors of Nrf2, GCLC, and NQO1 [128].
Supplementary antioxidants including N-acetylcysteine (NAC) [129,130] and alpha-lipoic acid [131] are also being investigated to reduce cisplatin-induced oxidative stress by Nrf2 activation. In the 2019 study by Güntürk et al., rats treated with 250 mg/kg NAC along with 10 mg/kg cisplatin showed a significant increase in the levels of myeloperoxidase-1 (MPO1) and high mobility group box-1 (HMGB-1) as well as ameliorated structural and functional changes in renal tissues [130]. Additionally, preclinical studies with α-lipoic acid (LA) suggested protection against cisplatin cytotoxicity via activation of the Nrf2/HO-1 pathway [131]. LA was also shown to induce the nuclear translocation of Nrf2 as well as include the expression of SOD1 protecting mice against oxidative stress [131].
Several dietary phytochemicals and natural compounds have been investigated as modulators of Nrf2 for prevention against cisplatin-induced injury including quercetin [132], resveratrol [133], curcumin [134], and catechins. Quercetin, a bioflavonoid shown to activate Nrf2 and HO-1 expression [135], has anti-inflammatory, antioxidant, and anticancer activities [136]. Quercetin mitigates cisplatin-induced nephrotoxicity in Fischer rats with breast adenocarcinoma without compromising the antitumor activity [132]. This study showed that treatment with quercetin markedly decreased levels of urinary KIM-1 and Gamma-glutamyl transpeptidase (GGT) suggesting decreased tubular damage [132]. Curcumin, another dietary antioxidant with nephroprotective properties, has been shown not to protect against cisplatin-induced kidney damage by ameliorating the levels of TNF-α, IL-6, KIM-1, NGAL, and Bax/Bcl-2 ratio in renal tissues [134].
This entry is adapted from the peer-reviewed paper 10.3390/antiox12091728
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