• Long non coding RNA : Potential players in cardiotoxicity induced by chemotherapy drug
  • Mehran Amrovani,1,* Mohmmad Javad Mohammadtaghizadeh,2 Mahsa Karimzadeh Aghaali,3 Somayeh Zamanifard,4 Arash Alqasi,5 Mozhdeh Sanaei,6
    1. Iranian Blood Transfusion Organization
    2. Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
    3. Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
    4. Departement of Cardiology, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
    5. Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
    6. Medicine student, Student Research Committee, Faculty of medicine, Shiraz University of Medical Sciences, Shiraz, I. R, Iran.


  • Introduction: One of the most important side effects of chemotherapy is cardiovascular complications, such as cardiotoxicity. Many factors are involved in the pathogenesis of cardiotoxicity; one of the most important of which is long non-coding RNAs (lncRNAs). lncRNA has 200-1000 nucleotides. It is involved in important processes such as cell proliferation, regeneration and apoptosis; today it is used as a prognostic and diagnostic factor. Also, various drugs by acting on lncRNAs can affect cells. Therefore, by accurately identifying IncRNAs function, we can play an effective role in preventing the development of cardiotoxicity induced chemotherapy drugs, and use them as a therapeutic strategy to improve clinical symptoms and Increase patient survival.
  • Methods: Electronic databases, including EMBASE, PubMed and Scopus
  • Results: Different chemotherapy drugs can play effective role in drug-induced cardiotoxicity. Cardiotoxicity induced by chemotherapy drugs occurs following the aging of the heart muscle cells. Some actions occur during the process of aging, including: decrease cell proliferation, P53 and P16 proteins expression increment, decrease telomere length and telomerase activity. In these processes, lncRNA plays an important role as a regulatory molecule, so shutting down the lncRNA molecule plays a protective role against the aging of heart cells, and lead to drug-induced cardiotoxicity. In addition, lncRNA can induce toxicity in cells by inhibiting proliferation, inducing apoptosis, and producing reactive oxygen species (ROS). Thus, lncRNA via PI3K / AKT pathway can induce apoptosis and ROS production, and subsequently induce cell toxicity via Notch1 / KLF15 pathway by inhibiting cell proliferation . Studies have also shown, that lncRNA can lead to Cardiovascular Disease (CVD) through toxin induction in cardiac muscle cells. Thus, lncRNA Cfast can trigger the TGF-β signaling pathway by inhibiting the interaction of COLT1 with the TRAP1 molecule; subsequently, by increasing the formation of SMAD2 / SMAD4 complexes, it induces fibrosis and finally toxicity in cardio myocytes, the product of which can be CVD induction. Also FOXD3-AS1 lncRNA can induce the phenomenon of Cisplatin chemoresistance by suppressing the miR-127-3P and increasing the MDM2 molecule expression. On the other hand, Drugs derived from Taxanes compounds such as Paclitaxel and Docetaxel as well as Adriamycin can reduce the proliferation of cancer cells by suppressing lncRNA MALAT1 and induce the effect of these drugs on these cells. Studies have shown that inhibition of ZEB1-AS1 lncRNA is required for the effect of Cisplatin on cancer cells. Inhibition of ZEB1-AS1 lncRNA in cancer cells leads to upregulation of miR-129-5P and subsequently inhibits cell proliferation and apoptosis induction in cancer cells through the inhibition of ZEB1 and bcl2 molecules. Considering the role of ZEB1-AS1 lncRNA in cell proliferation, including cardiac muscle cells, it is hypothesized that Cisplatin drug needs to inhibit ZEB1-AS1 lncRNA to induce its effect on cancer cells. Consequently, one of the side effects of this chemotherapy drug is probably cardiotoxicity; it happens by reducing the expression of ZEB1-AS1 lncRNA and inhibiting its function in the proliferation of cardio myocytes. Other Studies have also shown, that SOX2-OT lncRNA can intensify the induction of cellular apoptosis by Doxorubicin in cardio myocytes by targeting the miR-942-5P / DP5 pathway. Unlike SOX2-OT lncRNA, NEAT1 lncRNA by degrading miR-221-3P can prevent Doxorubicin-induced cardiac senescence in cardio myocytes; thereby it inhibits cardiotoxicity, whereas lncRNA SOX2-OT could be due to the effect of Doxorubicin inducing apoptosis in cardio myocytes. In addition Downregulation of lncRNA H19 can induce the effect of temozolomide on cancer cells by reducing the proliferation by suppressing the Wnt / β-Catenin pathway. on the other hand MT1JP lncRNA can induce the Cisplatin effect on cancer cells by inhibiting miR-24-3P and suppressing the Wnt / Beta-Catenin pathway in these cells. Due to the inhibitory role of this lncRNA in the cell proliferation, Cisplatin can lead to cardiotoxicity by inducing this lncRNA in cardio myocytes by inhibiting the cell proliferation. Also Expression of SNGH lncRNA can induce drug resistance to Sunitinib in the cancer cells through upregulation of CDCA3 molecule.
  • Conclusion: lncRNAs play an important role in the cardiotoxicity induced by chemotherapy drugs. Therefore, the identification of signaling pathways by lncRNAs that lead to the induction of cardiotoxicity by chemotherapy drugs can be used to design appropriate target therapies to minimize the cardiac complication of chemotherapy-related toxicity.
  • Keywords: Long Non-coding RNAs, Cardiotoxicity, Cardiomyocyte, Mechanism