Chemical screening identifies the β-Carboline alkaloid harmine to be synergistically lethal with doxorubicin.
Despite being an invaluable chemotherapeutic agent for several types of cancer, the clinical utility of doxorubicin is hampered by its age-related and dose-dependent cardiotoxicity. Co-administration of dexrazoxane as a cardioprotective agent has been proposed, however recent studies suggest that it attenuates doxorubicin-induced antitumor activity. Since compounds of natural origin present a rich territory for drug discovery, we set out to identify putative natural compounds with the view to mitigate or minimize doxorubicin cardiotoxicity. We identify the DYRK1A kinase inhibitor harmine, which phosphorylates Tau that is deregulated in Alzheimer's disease, as a potentiator of cell death induced by non-toxic doses of doxorubicin. These observations suggest that harmine or other compounds that target the DYRK1A kinase my offer a new therapeutic opportunity to suppress doxorubicin age-related and dose-dependent cardiotoxicity.
Center of Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
Reham
R
Atteya
Center of Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
Mohamed E
ME
Ashour
Center of Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
Elsayed E
EE
Ibrahim
Deparrtment of Pharamcognosy, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
Mohamed A
MA
Farag
Center of Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt; Krebs Institute, University of Sheffield, Sheffield, S10 2TN, UK. Electronic address: s.el-khamisy@sheffield.ac.uk.
Sherif F
SF
El-Khamisy
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D004317:Doxorubicin / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006247:Harmine / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097603:Dyrk Kinases
D004317:Doxorubicin; D006247:Harmine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016875:tau Proteins; D000097603:Dyrk Kinases
Cardiotoxicity; DYRK1A kinase; Doxorubicin; Harmine; Natural products; TOP2