The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells
نویسندگان
چکیده
Epigenetic therapies have emerged as promising anticancer approaches, since epigenetic modifications play a major role in tumor initiation and progression. Hydralazine, an approved vasodilator and antihypertensive drug, has been recently shown to act as a DNA methylation inhibitor. Even though hydralazine is already tested in clinical cancer trials, its mechanism of antitumor action remains undefined. Here, we show that hydralazine induced caspase-dependent apoptotic cell death in human p53-mutant leukemic T cells. Moreover, we demonstrate that hydralazine triggered the mitochondrial pathway of apoptosis by inducing Bak activation and loss of the mitochondrial membrane potential. Hydralazine treatment further resulted in the accumulation of reactive oxygen species, whereas a superoxide dismutase mimetic inhibited hydralazine-induced cell death. Interestingly, caspase-9-deficient Jurkat cells or Bcl-2- and Bcl-xL-overexpressing cells were strongly resistant to hydralazine treatment, thereby demonstrating the dependence of hydralazine-induced apoptosis on the mitochondrial death pathway. Furthermore, we demonstrate that hydralazine treatment triggered DNA damage which might contribute to its antitumor effect.
منابع مشابه
Umbelliprenin from Ferula szowitsiana Activates both Intrinsic and Extrinsic Pathways of Apoptosis in Jurkat T-CLL Cell Line
Umbelliprenin is a prenylated compound, which belongs to the class of sesquiterpene coumarins. It is extracted from dried roots of Ferula szwitsiana collected from the mountains of Golestan forest (Golestan Province, north of Iran). Induction of apoptosis in Jurkat T-CLL cells has been previously shown. In this study, effect of umbelliprenin on proapoptotic caspases (caspase-8 and -9) and antia...
متن کاملUmbelliprenin from Ferula szowitsiana Activates both Intrinsic and Extrinsic Pathways of Apoptosis in Jurkat T-CLL Cell Line
Umbelliprenin is a prenylated compound, which belongs to the class of sesquiterpene coumarins. It is extracted from dried roots of Ferula szwitsiana collected from the mountains of Golestan forest (Golestan Province, north of Iran). Induction of apoptosis in Jurkat T-CLL cells has been previously shown. In this study, effect of umbelliprenin on proapoptotic caspases (caspase-8 and -9) and antia...
متن کاملبررسی اثرات ضد تکثیری داروی هیدرالازین بر روی سلولهای سرطانی رده K562 (لوسمی میلوئید مزمن)اثر هیدرالازین بر سلولهای K562
Introduction: Cancer is the second leading cause of death in the world and among the types of cancer, leukemia is one of the deadliest. Chronic myeloid leukemia (CML) is the best known types of leukemia. Hydralazine is in the cardiovascular medical group, which is considering as inhibitory factor on the proliferation of cancer cells by knowing its inhibitory effects on DNA methyltransferase. Th...
متن کاملSynergistic Effects of Arsenic Trioxide and Radiation: Triggering the Intrinsic Pathway of Apoptosis
Background: Arsenic trioxide (ATO) has been reported as an effective anti-cancer and a US Food and Drug Administration (FDA) approved drug for treatment of some cancers. The aim of this study is to determine the underlying apoptosis molecular and cellular mechanisms of ATO in the presence or absence of ionizing radiation (IR) in vitro in the glioblastoma multiforme (GBM) cell line, U87MG. Metho...
متن کاملEffects of Trichostatin A on the Histone Deacetylases (HDACs), Intrinsic Apoptotic Pathway, p21/Waf1/Cip1, and p53 in Human Neuroblastoma, Glioblastoma, Hepatocellular Carcinoma, and Colon Cancer Cell Lines
Background: The aberrant and altered patterns of gene expression play an important role in the biology of cancer and tumorigenesis. DNA methylation and histone deacetylation are the most studied epigenetic mechanisms. Histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA) and trichostatin A (TSA) are a group of anticancer compounds for the treatment of solid and hematological canc...
متن کامل