Skip to main content
Log in

Micheliolide Protects Against Doxorubicin-Induced Cardiotoxicity in Mice by Regulating PI3K/Akt/NF-kB Signaling Pathway

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Micheliolide (MCL) is a naturally derived anti-inflammatory agent. In the present investigation, we examined the protective potential of MCL against doxorubicin (DOX)-induced cardiotoxicity in mice. Mice were injected with a single 15-mg/kg intraperitoneal dose of DOX at day 1 and the study groups received daily 12.5, 25, and 50 mg/kg doses of MCL for 7 days. Cardiac histopathology, cardiac function, serum markers of cardiac injury, and tissue markers of inflammation, and oxidative stress were examined. MCL decreased serum levels of creatinine kinase MB (CK-MB) and cardiac troponin I (cTnI) levels, ameliorated cardiac tissue architecture, and improved cardiac stroke volume. Apart from reducing the activities of NF-kB p65 subunit, MCL attenuated the cardiac levels of PI3K, phosphorylated (p)-Akt, p-Bad, and caspase-3 levels and simultaneously elevated p-PTEN levels. While the gene expressions of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) were decreased, the tissue activities of superoxide dismutase (SOD) as well as gene expressions of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase-1 (NQO1) were increased after treatment with MCL. Furthermore, tissue levels of malondialdehyde (MDA) were also decreased. Collectively, these findings point to the protective effects of MCL against DOX-induced cardiotoxicity by regulating PI3K/Akt/NF-kB signaling pathway in mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. McGowan, J. V., Chung, R., Maulik, A., Piotrowska, I., Walker, J. M., & Yellon, D. M. (2017). Anthracycline chemotherapy and cardiotoxicity. Cardiovascular Drugs and Therapy, 31, 63–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rahman, A. M., Yusuf, S. W., & Ewer, M. S. (2007). Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation. International Journal of Nanomedicine, 2, 567.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Volkova, M., & Russell, R. (2011). Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Current Cardiology Reviews, 7, 214–220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. de Oliveira Silva, J., Miranda, S. E. M., Leite, E. A., de Paula Sabino, A., Borges, K. B. G., Cardoso, V. N., Cassali, G. D., Guimarães, A. G., Oliveira, M. C., & de Barros, A. L. B. (2018). Toxicological study of a new doxorubicin-loaded pH-sensitive liposome: A preclinical approach. Toxicology and Applied Pharmacology, 352, 162–169

    Article  CAS  Google Scholar 

  5. Renu, K., Abilash, V., Pichiah, P. T., & Arunachalam, S. (2017). Molecular mechanism of doxorubicin-induced cardiomyopathy: An update. European Journal of Pharmacology, 818, 241–253

    Google Scholar 

  6. De Angelis, A., Urbanek, K., Cappetta, D., Piegari, E., Ciuffreda, L. P., Rivellino, A., Russo, R., Esposito, G., Rossi, F., & Berrino, L. (2016). Doxorubicin cardiotoxicity and target cells: A broader perspective. Cardio-Oncology, 2, 2.

    Article  Google Scholar 

  7. Viennois, E., Xiao, B., Ayyadurai, S., Wang, L., Wang, P. G., Zhang, Q., Chen, Y., & Merlin, D. (2014). Micheliolide, a new sesquiterpene lactone that inhibits intestinal inflammation and colitis-associated cancer. Laboratory Investigation, 94, 950.

    Article  CAS  PubMed  Google Scholar 

  8. Sun, Z., Li, G., Tong, T., & Chen, J. (2017). Micheliolide suppresses LPS-induced neuroinflammatory responses. PLoS ONE, 12, e0186592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang, Q., Jiang, X., He, W., Wei, K., Sun, J., Qin, X., Zheng, Y., & Jiang, X. (2017). MCL plays an anti-inflammatory role in mycobacterium tuberculosis-induced immune response by inhibiting NF-κB and NLRP3 inflammasome activation. Mediators of Inflammation. https://doi.org/10.1155/2017/2432904.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhong, J., Gong, W., Chen, J., Qing, Y., Wu, S., Li, H., Huang, C., Chen, Y., Wang, Y., & Xu, Z. (2018). Micheliolide alleviates hepatic steatosis in db/db mice by inhibiting inflammation and promoting autophagy via PPAR-γ-mediated NF-кB and AMPK/mTOR signaling. International Immunopharmacology, 59, 197–208.

    Article  CAS  PubMed  Google Scholar 

  11. Montgomery, M. D., Chan, T., Swigart, P. M., Myagmar, B., Dash, R., & Simpson, P. C. (2017). An alpha-1A adrenergic receptor agonist prevents acute doxorubicin cardiomyopathy in male mice. PLoS ONE, 12, e0168409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mantawy, E. M., El-Bakly, W. M., Esmat, A., Badr, A. M., & El-Demerdash, E. (2014). Chrysin alleviates acute doxorubicin cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. European Journal of Pharmacology, 728, 107–118.

    Article  CAS  PubMed  Google Scholar 

  13. Govender, J., Loos, B., Marais, E., & Engelbrecht, A.-M. (2018). Melatonin improves cardiac and mitochondrial function during doxorubicin-induced cardiotoxicity: A possible role for peroxisome proliferator-activated receptor gamma coactivator 1-alpha and sirtuin activity? Toxicology and Applied Pharmacology, 358, 86–101

    Article  CAS  Google Scholar 

  14. Zhu, Z., Zhao, Y., Huo, H., Gao, X., Zheng, J., Li, J., & Tu, P. (2016). HHX-5, a derivative of sesquiterpene from Chinese agarwood, suppresses innate and adaptive immunity via inhibiting STAT signaling pathways. European Journal of Pharmacology, 791, 412–423.

    Article  CAS  PubMed  Google Scholar 

  15. Amoah, S. K., Dalla Vecchia, M. T., Pedrini, B., Carnhelutti, G. L., Gonçalves, A. E., dos Santos, D. A., Biavatti, M. W., & de Souza, M. M. (2015). Inhibitory effect of sesquiterpene lactones and the sesquiterpene alcohol aromadendrane-4β, 10α-diol on memory impairment in a mouse model of Alzheimer. European Journal of Pharmacology, 769, 195–202.

    Article  CAS  PubMed  Google Scholar 

  16. Lai, L., Chen, Y., Tian, X., Li, X., Zhang, X., Lei, J., Bi, Y., Fang, B., & Song, X. (2015). Artesunate alleviates hepatic fibrosis induced by multiple pathogenic factors and inflammation through the inhibition of LPS/TLR4/NF-κB signaling pathway in rats. European Journal of Pharmacology, 765, 234–241.

    Article  CAS  PubMed  Google Scholar 

  17. Zhang, X.-W., Wang, S., Tu, P.-F., & Zeng, K.-W. (2018). Sesquiterpene lactone from Artemisia argyi induces gastric carcinoma cell apoptosis via activating NADPH oxidase/reactive oxygen species/mitochondrial pathway. European Journal of Pharmacology, 837, 164–170

    Google Scholar 

  18. Zhuang, Z., Zhao, X., Wu, Y., Huang, R., Zhu, L., Zhang, Y., & Shi, J. (2011). The anti-apoptotic effect of PI3K-Akt signaling pathway after subarachnoid hemorrhage in rats. Annals of Clinical & Laboratory Science, 41, 364–372.

    CAS  Google Scholar 

  19. Kitamura, Y., Koide, M., Akakabe, Y., Matsuo, K., Shimoda, Y., Soma, Y., Ogata, T., Ueyama, T., Matoba, S., & Yamada, H. (2014). Manipulation of cardiac phosphatidylinositol 3-kinase (PI3K)/Akt signaling by apoptosis regulator through modulating IAP expression (ARIA) regulates cardiomyocyte death during doxorubicin-induced cardiomyopathy. Journal of Biological Chemistry, 289, 2788–2800.

    Article  CAS  PubMed  Google Scholar 

  20. Yu, W., Sun, H., Zha, W., Cui, W., Xu, L., Min, Q., & Wu, J. (2017). Apigenin attenuates adriamycin-induced cardiomyocyte apoptosis via the PI3K/AKT/mTOR pathway. Evidence-Based Complementary and Alternative Medicine. https://doi.org/10.1155/2017/2590676

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cao, Y., Ruan, Y., Shen, T., Huang, X., Li, M., Yu, W., Zhu, Y., Man, Y., Wang, S., & Li, J. (2014). Astragalus polysaccharide suppresses doxorubicin-induced cardiotoxicity by regulating the PI3k/Akt and p38MAPK pathways. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2014/674219

    Article  PubMed  PubMed Central  Google Scholar 

  22. Virdee, K., Parone, P., & Tolkovsky, A. (2000). Phosphorylation of the pro-apoptotic protein BAD on serine 155, a novel site, contributes to cell survival. Current Biology, 10, 1151–1154.

    Article  CAS  PubMed  Google Scholar 

  23. Wolf, B. B., Schuler, M., Echeverri, F., & Green, D. R. (1999). Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation. Journal of Biological Chemistry, 274, 30651–30656.

    Article  CAS  PubMed  Google Scholar 

  24. Liu, T., Zhang, L., Joo, D., & Sun, S.-C. (2017). NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy, 2, 17023.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Guo, R.-M., Xu, W.-M., Lin, J.-C., Mo, L.-Q., Hua, X.-X., Chen, P.-X., Wu, K., Zheng, D.-D., & Feng, J.-Q. (2013). Activation of the p38 MAPK/NF-κB pathway contributes to doxorubicin-induced inflammation and cytotoxicity in H9c2 cardiac cells. Molecular Medicine Reports, 8, 603–608.

    Article  PubMed  Google Scholar 

  26. Ho, W. C., Dickson, K. M., & Barker, P. A. (2005). Nuclear factor-κB induced by doxorubicin is deficient in phosphorylation and acetylation and represses nuclear factor-κB-dependent transcription in cancer cells. Cancer Research, 65, 4273–4281.

    Article  CAS  PubMed  Google Scholar 

  27. Sims, J. T., Ganguly, S. S., Bennett, H., Friend, J. W., Tepe, J., & Plattner, R. (2013). Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS ONE, 8, e55509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Romano, M. F., Avellino, R., Petrella, A., Bisogni, R., Romano, S., & Venuta, S. (2004). Rapamycin inhibits doxorubicin-induced NF-κB/Rel nuclear activity and enhances the apoptosis of melanoma cells. European Journal of Cancer, 40, 2829–2836.

    Article  CAS  PubMed  Google Scholar 

  29. Bai, D., Ueno, L., & Vogt, P. K. (2009). Akt-mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt. International journal of cancer, 125, 2863–2870.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Balwani, S., Chaudhuri, R., Nandi, D., Jaisankar, P., Agrawal, A., & Ghosh, B. (2012). Regulation of NF-κB activation through a novel PI-3K-independent and PKA/Akt-dependent pathway in human umbilical vein endothelial cells. PLoS ONE, 7, e46528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cappetta, D., De Angelis, A., Sapio, L., Prezioso, L., Illiano, M., Quaini, F., Rossi, F., Berrino, L., Naviglio, S., & Urbanek, K. (2017). Oxidative stress and cellular response to doxorubicin: A common factor in the complex milieu of anthracycline cardiotoxicity. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2017/1521020

    Article  PubMed  PubMed Central  Google Scholar 

  32. Shaker, R. A., Abboud, S. H., Assad, H. C., & Hadi, N. (2018). Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. BMC Pharmacology and Toxicology, 19, 3.

    Article  CAS  PubMed  Google Scholar 

  33. Asensio-López, M. C., Soler, F., Pascual-Figal, D., Fernández-Belda, F., & Lax, A. (2017). Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes. PLoS ONE, 12, e0172803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vupputuri, A., Sekhar, S., Krishnan, S., Venugopal, K., & Natarajan, K. (2015). Heart-type fatty acid-binding protein (H-FABP) as an early diagnostic biomarker in patients with acute chest pain. Indian Heart Journal, 67, 538–542.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Lippi, G., Mattiuzzi, C., Comelli, I., & Cervellin, G. (2013). Glycogen phosphorylase isoenzyme BB in the diagnosis of acute myocardial infarction: A meta-analysis. Biochemia Medica, 23, 78–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mythili, S., & Malathi, N. (2015). Diagnostic markers of acute myocardial infarction. Biomedical Reports, 3, 743–748.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Van Norren, K., Van Helvoort, A., Argiles, J., Van Tuijl, S., Arts, K., Gorselink, M., Laviano, A., Kegler, D., Haagsman, H., & Van Der Beek, E. (2009). Direct effects of doxorubicin on skeletal muscle contribute to fatigue. British Journal of Cancer, 100, 311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tangpong, J., Miriyala, S., Noel, T., Sinthupibulyakit, C., Jungsuwadee, P., & Clair, D. S. (2011). Doxorubicin-induced central nervous system toxicity and protection by xanthone derivative of Garcinia mangostana. Neuroscience, 175, 292–299.

    Article  CAS  PubMed  Google Scholar 

  39. Kalender, Y., Yel, M., & Kalender, S. (2005). Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats: The effects of vitamin E and catechin. Toxicology, 209, 39–45.

    Article  CAS  PubMed  Google Scholar 

  40. Batatinha, H., Souza, C., Lima, E., Alonso-Vale, M. I., Cruz, M., Da Cunha, R., Lira, F., & Rosa, J. (2014). Adipose tissue homeostasis is deeply disrupted by doxorubicin treatment. Cancer & Metabolism, 2, P5.

    Article  Google Scholar 

  41. Wu, A. H., Panteghini, M., Apple, F., Christenson, R., Dati, F., & Mair, J. (1999). Biochemical markers of cardiac damage: From traditional enzymes to cardiac-specific proteins. Scandinavian Journal of Clinical and Laboratory Investigation, 59, 74–82.

    Article  Google Scholar 

  42. Kemp, M., Donovan, J., Higham, H., & Hooper, J. (2004). Biochemical markers of myocardial injury. British Journal of Anaesthesia, 93, 63–73.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the grant from the Student Research Committee, Tabriz University of Medical Sciences.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Saeed Nazari Soltan Ahmad.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Handling Editor: Dipak K Dube

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kalantary-Charvadeh, A., Sanajou, D., Hemmati-Dinarvand, M. et al. Micheliolide Protects Against Doxorubicin-Induced Cardiotoxicity in Mice by Regulating PI3K/Akt/NF-kB Signaling Pathway. Cardiovasc Toxicol 19, 297–305 (2019). https://doi.org/10.1007/s12012-019-09511-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-019-09511-2

Keywords

Navigation