Cardioprotective effect of phytosterol stigmasterol supplementation against doxorubicin-induced cardiotoxicity
Abstract
Background and objectives: Stigmasterol, a phytosterol abundantly found in various plant sources, including soybeans and other legumes, plays a significant pharmaceutical role due to its pharmacological properties. Research suggests that stigmasterol exhibits anti-inflammatory, antioxidant, and cholesterol-lowering effects, making it a promising candidate for managing cardiovascular disorders. In this work, we elucidated the cardioprotective potency of stigmasterol against doxorubicin-induced cardiotoxicity in rats.
Materials and methods: Hence we have evaluated the potency of stigmasterol supplementation in preventing doxorubicin-induced cardiotoxicity. Male Wistar rats were treated with doxorubicin (2.5 mg/kg) and supplemented with 25 and 50 mg/kg doses of stigmasterol for 14 days. On 14th day of treatment tail-cuff plethysmography was conducted to assess the hemodynamic parameters. The concentrations of oxidative stress markers, cardiac function markers, myocardial damage markers, and inflammatory biomarkers were assessed in the experimental rats using the commercial kits. The heart tissues were subjected to the histopathological analysis. Docking study was also conducted with NF-κB.
Results: The stigmasterol treatment effectively increased the body weight and heart weight and elevated the hemodynamic parameters in doxorubinin-induced rats. The stigmasterol treatment also decreased the oxidative stress via increasing antioxidants, reduced the cardiac function markers, and decreased the myocardial damage markers in the doxorubicin-induced rats. Furthermore, the stigmasterol treatment also reduced the inflammatory markers in the doxorubicin-induced rats. The cardioprotective properties of the stigmasterol was further supported by the results of histopathological analysis and docking analysis where it showed excellent binding affinity for NF-κB.
Conclusions: The results of tail-cuff plethysmography and cardiac tissue histopathological analysis authentically proved the inhibitory effect of stigmasterol against doxorubicin induced cardiotoxicity. To conclude supplementation with phytochemical stigmasterol persuasively ameliorated doxorubicin induced cardiotoxicity.
Keywords: anticancer drugdoxorubicincardiotoxicityphytosterolstigmasterolsupplementary drug
References
- Abushouk AI, Ismail A, Salem AM, et al. Cardioprotective mechanisms of phytochemicals against doxorubicin-induced cardiotoxicity. Biomed Pharmacother. 2017; 90: 935–946.
- Babuin L, Jaffe AS. Troponin: the biomarker of choice for the detection of cardiac injury. CMAJ. 2005; 173(10): 1191–1202.
- Bakrim S, Benkhaira N, Bourais I, et al. Health benefits and pharmacological properties of stigmasterol. Antioxidants (Basel). 2022; 11(10).
- Bhagat A, Shrestha P, Kleinerman ES. The innate immune system in cardiovascular diseases and its role in doxorubicin-induced cardiotoxicity. Int J Mol Sci. 2022; 23(23).
- Biondo LA, Lima Junior EA, Souza CO, et al. Impact of doxorubicin treatment on the physiological functions of white adipose tissue. PLoS One. 2016; 11(3): e0151548.
- Brooijmans N, Kuntz ID. Molecular recognition and docking algorithms. Annu Rev Biophys Biomol Struct. 2003; 32: 335–373.
- Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020; 17(7): 395–417.
- Chau LY. Heme oxygenase-1: emerging target of cancer therapy. J Biomed Sci. 2015; 22(1): 22.
- Chen WP, Yu C, Hu PF, et al. Stigmasterol blocks cartilage degradation in rabbit model of osteoarthritis. Acta Biochim Pol. 2012; 59(4): 537–541.
- Chiang SK, Chen SE, Chang LC. A dual role of heme oxygenase-1 in cancer cells. Int J Mol Sci. 2018; 20(1).
- Chiang SK, Chen SE, Chang LC. The role of HO-1 and its crosstalk with oxidative stress in cancer cell survival. Cells. 2021; 10(9).
- Ferlay J, Colombet M, Soerjomataram I, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019; 144(8): 1941–1953.
- Hanna A, Frangogiannis NG. The role of the TGF-β superfamily in myocardial infarction. Front Cardiovasc Med. 2019; 6: 140.
- Kant UR. Antihyperlipidemic and cardioprotective effects of plant natural products: a review. Int J Green Pharm. 2021; 15(1): 1–19.
- Kciuk M, Gielecińska A, Mujwar S, et al. Doxorubicin — an agent with multiple mechanisms of anticancer activity. Cells. 2023; 12(4).
- Liu C, Ma X, Zhuang J, et al. Cardiotoxicity of doxorubicin-based cancer treatment: What is the protective cognition that phytochemicals provide us? Pharmacol Res. 2020; 160: 105062.
- Liu Y, Grimm M, Dai WT, et al. CB-Dock: a web server for cavity detection-guided protein-ligand blind docking. Acta Pharmacol Sin. 2020; 41(1): 138–144.
- Liu Y, Yang X, Gan J, et al. CB-Dock2: improved protein-ligand blind docking by integrating cavity detection, docking and homologous template fitting. Nucleic Acids Res. 2022; 50(W1): W159–W164.
- Masih A, Agnihotri AK, Srivastava JK, et al. Discovery of novel pyrazole derivatives as a potent anti-inflammatory agent in RAW264.7 cells via inhibition of NF-ĸB for possible benefit against SARS-CoV-2. J Biochem Mol Toxicol. 2021; 35(3): e22656.
- Mohammadi M, Arabi L, Alibolandi M. Doxorubicin-loaded composite nanogels for cancer treatment. J Control Release. 2020; 328: 171–191.
- Nabati M, Janbabai G, Baghyari S, et al. Cardioprotective effects of carvedilol in inhibiting doxorubicin-induced cardiotoxicity. J Cardiovasc Pharmacol. 2017; 69(5): 279–285.
- Othman S, Lum P, Gan S, et al. Protective effect of natural products against chemotherapy-induced cardiotoxicity: a review. Pharmacog J. 2020; 12(5): 1180–1189.
- Octavia Y, Tocchetti CG, Gabrielson KL, et al. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012; 52(6): 1213–1225.
- Oh ET, Park HJ. Implications of NQO1 in cancer therapy. BMB Rep. 2015; 48(11): 609–617.
- Pagadala NS, Syed K, Tuszynski J. Software for molecular docking: a review. Biophys Rev. 2017; 9(2): 91–102.
- Preethi S, Arthiga K, Patil AB, et al. Review on NAD(P)H dehydrogenase quinone 1 (NQO1) pathway. Mol Biol Rep. 2022; 49(9): 8907–8924.
- Ruiz-Ortega M, Rodríguez-Vita J, Sanchez-Lopez E, et al. TGF-beta signaling in vascular fibrosis. Cardiovasc Res. 2007; 74(2): 196–206.
- Sheibani M, Azizi Y, Shayan M, et al. Doxorubicin-induced cardiotoxicity: an overview on pre-clinical therapeutic approaches. Cardiovasc Toxicol. 2022; 22(4): 292–310.
- Skovgaard D, Hasbak P, Kjaer A. BNP predicts chemotherapy-related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography. PLoS One. 2014; 9(5): e96736.
- Songbo M, Lang H, Xinyong C, et al. Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett. 2019; 307: 41–48.
- Srivastava J, Awatade N, Bhat H, et al. Pharmacological evaluation of hybrid thiazolidin-4-one-1,3,5-triazines for NF-κB, biofilm and CFTR activity. RSC Advances. 2015; 5(108): 88710–88718.
- Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3): 209–249.
- Syukri A, Hatta M, Amir M, et al. Doxorubicin induced immune abnormalities and inflammatory responses via HMGB1, HIF1-α and VEGF pathway in progressive of cardiovascular damage. Ann Med Surg (Lond). 2022; 76: 103501.
- Tie Y, Tang F, Peng D, et al. TGF-beta signal transduction: biology, function and therapy for diseases. Mol Biomed. 2022; 3(1): 45.
- Wang L, Chen Q, Qi H, et al. Doxorubicin-Induced systemic inflammation is driven by upregulation of toll-like receptor TLR4 and endotoxin leakage. Cancer Res. 2016; 76(22): 6631–6642.
- Webster JM, Kempen LJ, Hardy RS, et al. Inflammation and skeletal muscle wasting during cachexia. Front Physiol. 2020; 11: 597675.
- Wells SM, Sleeper M. Cardiac troponins. J Vet Emerg Critical Care. 2008; 18(3): 235–245.
- Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009; 9(1): 28–39.
- Zhang X, Wang J, Zhu L, et al. Advances in stigmasterol on its anti-tumor effect and mechanism of action. Front Oncol. 2022; 12: 1101289.
- Zhang YW, Shi J, Li YJ, et al. Cardiomyocyte death in doxorubicin-induced cardiotoxicity. Arch Immunol Ther Exp. 2009; 57(6): 435–445.
