Exploring the cardioprotective effects of canagliflozin against cisplatin‐induced cardiotoxicity: Role of iNOS/NF‐κB, Nrf2, and Bax/cytochrome C/Bcl‐2 signals

Abstract

Cardiotoxicity is a severe considerable side effect of cisplatin (CDDP) that requires much medical attention. The current study investigates the cardioprotective effects of canagliflozin (CA) against CDDP-induced heart toxicity. Rats were allocated to the control group; the CA group was administered CA 10 mg/kg/day orally for 10 days; the CDDP group was injected with 7 mg/kg, intraperitoneal as a single dose on the 5th day, and the CDDP + CA group. Compared to the CDDP-treated group, CA effectively attenuated CDDP-induced heart injury as evidenced by a decrease of serum aspartate aminotransferase, alkaline phosphatase, creatine kinase-MB, and lactate dehydrogenase enzymes and supported by the alleviation of histopathological changes in cardiac tissues. Biochemically, CA attenuated cardiac oxidative injury through upregulation of the nuclear factor-erythroid 2 related factor 2 (Nrf2) signal. CA suppressed inflammation by decreasing cardiac NO 2 − , MPO, iNOS, nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha, and interleukin 1-beta levels. Besides, CA significantly upregulated cardiac levels of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and p-AKT proteins. Moreover, CA remarkably mitigated CDDP-induced apoptosis via modulation of Bax, cytochrome C, and Bcl-2 protein levels. Together, the present study revealed that CA could be a good candidate for preventing CDDP-induced cardiac injury by modulating iNOS/NF-κB, Nrf2, PI3K/AKT, and Bax/cytochrome C/Bcl-2 signals.

The Cardioprotective and Anticancer Effects of SGLT2 Inhibitors

“…Subsequent to landmark studies demonstrating the cardioprotective effects of SGLT2 inhibitors in HF, numerous in vivo ( Table 2 ) and in vitro ( Table 3 ) studies, starting in 2019, have underscored the cardioprotective roles of SGLT2 inhibitors in mitigating cardiotoxicity induced by various cancer treatments, including DOX, 17 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 sunitinib, 20 trastuzumab, 21 cisplatin, 19 ipilmumab, 54 , 55 ponatinib, 56 and carfilzomib. 57 DOX has received particular attention because of its status as the most cardiotoxic cancer treatment and its widespread use.…”

“…Empagliflozin 17 , 20 , 21 , 39 , 40 , 41 , 42 , 43 , 49 , 55 , 56 and dapagliflozin 44 , 45 , 46 , 48 , 50 , 51 , 52 , 53 , 54 , 56 have emerged as the most commonly used SGLT2 inhibitors, followed by canagliflozin. 19 , 57 Notably, no in vivo studies have reported the protective effects of canagliflozin against DOX, with only 1 in vivo study reporting the cardioprotective effects of canagliflozin against cisplatin 19 and an in vitro study demonstrating its efficacy against carfilzomib. 57 In vitro studies involved different types of cardiomyocytes, 21 , 47 as well as human aortic 56 and human umbilical vein endothelial cells.…”

“… EMPA (10 mg/kg twice per week for 6 wk, i.p.) ↑ EF, FS, ↓ LVESD Improved cardiomyocyte mechanical and intracellular dysfunction Preserved mitochondrial integrity and function ↓ Apoptosis, ferroptosis, DNA damage ↓ Oxidative stress ↓ Intracellular Ca 2+ decay rate ↑ Mitochondrial biogenesis (PGC-1α) Ali et al (2023) 19 Wistar albino rats Cisplatin (7 mg/kg, single dose, i.p.) CANA (10 mg/kg/d, oral) ↓ AST, ALP, CK-MB, LDH ↑ Nrf2 ↓ NO, MPO ↓ iNOS, NF-κB, TNF-a, IL-1β ↑ PI3K/AKT pathway ↓ Bax, Bcl-2, cytochrome c AKT = protein kinase B; ALP = alkaline phosphatase; α-SMA = α-smooth muscle actin; AMPK = adenosine monophosphate–activated protein kinase; ANP = atrial natriuretic peptide; ARN = angiotensin receptor neprilysin inhibitor; AST = aspartate aminotransferase; ATF-4 = activating transcription factor 4; Bax = Bcl-2-associated X protein; β-MHC = β-myosin heavy chain; βOHB = β-hydroxy butyrate; BNP = B-type natriuretic peptide; CAT = catalase; CFR = coronary flow reserve; CK-MB = creatine kinase MB; CRS = cardiorenal syndrome; cTnT = cardiac troponin T; DAMP = damage-associated molecular pattern; DOX = doxorubicin; ECG = electrocardiographic; EF = ejection fraction; eIF-2α = eukaryotic initiation factor 2α; ER = endoplasmic reticulum; ERK = extracellular signal-regulated kinase; FGF = fibroblast growth factor; FS = fractional shortening; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; GRP78 = glucose-regulated protein 78; HTN = hypertension; i.p.…”

“… 54 Recently, canagliflozin counteracted cisplatin-induced cardiotoxicity by reducing levels of nuclear factor κB, myeloperoxidase, inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin-1β. 19 …”

“…A plethora of preclinical studies, along with a growing number of observational clinical studies, have suggested promising cardioprotective roles for SGLT2 inhibitors in mitigating cancer treatment–related cardiotoxicity. 16 , 17 , 18 , 19 , 20 , 21 …”