PhD Student, Zewail City of Science and Technology
Investigating mechanisms to enhance the efficacy and reduce cardiotoxicity of doxorubicin
Anthracyclines are a class of cancer chemotherapeutics considered to be one of the most efficacious anti-tumor drugs ever developed. Doxorubicin is one of the first anthracyclines to be discovered where today, it is widely used clinically for several solid and liquid tumors. Doxorubicin is the first line treatment for breast cancer and also used for soft tissue sarcomas and aggressive lymphomas. The anti-tumorogenic properties of doxorubicin stems from targeting Topoisomerase II (TOP2); an essential cellular enzyme that is required for regulating DNA topology during various cellular processes such as transcription, replication and recombination. Chronic cardiomyopathy and congestive heart failure have been strongly associated with doxorubicin treatment. 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 identified harmine as a potentiator of cell death induced by non-toxic doses of doxorubicin on breast cancer cell lines in addition to a doxorubicin-resistant breast cancer cell line. Moreover, we have confirmed that the harmine-doxorubicin combination is not toxic on cardiomyocytes. These observations suggest that harmine may offer a new therapeutic opportunity to suppress doxorubicin’s dose-dependent cardiotoxicity. Currently, we aim to unveil the mechanism behind this synergistic activity and characterize whether this synergism would hold in vivo in a mouse tumor model.
Abstract: DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy.
Pub.: 30 May '13, Pinned: 31 Mar '18
Abstract: The mammalian genome is constantly challenged by exogenous and endogenous threats. Although much is known about the mechanisms that maintain DNA and RNA integrity, we know surprisingly little about the mechanisms that underpin the pathology and tissue specificity of many disorders caused by defective responses to DNA or RNA damage. Of the different types of endogenous damage, protein-linked DNA breaks (PDBs) are emerging as an important player in cancer development and therapy. PDBs can arise during the abortive activity of DNA topoisomerases, a class of enzymes that modulate DNA topology during several chromosomal transactions, such as gene transcription and DNA replication, recombination and repair. In this Review, we discuss the mechanisms underpinning topoisomerase-induced PDB formation and repair with a focus on their role during gene transcription and the development of tissue-specific cancers.
Pub.: 20 Feb '15, Pinned: 31 Mar '18
Abstract: 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.
Pub.: 06 Jun '16, Pinned: 31 Mar '18