title: Selective Anticancer Activity of Acacetin Against Chronic Lymphocytic Leukemia Using Both In Vivo and In Vitro Methods: Key Role of Oxidative Stress and Cancerous Mitochondria.
abstract: The present study investigates the in vitro and in vivo effect of acacetin (4'-methoxy-5,7-dihydroxyflavone) on chronic lymphocytic leukemia (CLL) B-lymphocytes and mitochondria. CLL B-lymphocytes and healthy B-lymphocytes were obtained from CLL patients and healthy donors, respectively. Mitochondria were isolated from B-lymphocytes of both groups. Xenografts in severe combined immune deficient mice were used to examine the toxicity and anti CLL activity of acacetin. We evaluated and compared the mechanism of action of acacetin on CLL and healthy B-lymphocytes and their mitochondria. We have found that acacetin (10 μM) can selectively induce apoptosis on CLL B-lymphocyte (25% at 24 h) by directly targeting mitochondria, through increased reactive oxygen species (ROS) formation, MMP collapse, MPT, release of cytochrome c, caspase 3 activation, and finally apoptosis, while sparing normal healthy B-lymphocytes unaffected at similar concentrations. Besides, oral administration of acacetin showed a potent in vivo anticancer activity in CLL xenograft mouse models. Our in vivo findings indicate that acacetin accumulates and kills CLL B-lymphocyte in a rather selective way through targeting cancerous mitochondria and ROS formation, which ends in CLL therapy. Finally, we can recommend acacetin as a promising compound for further drug development assays for the CLL treatment.
authors: a Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences , Tehran , Iran ; Department of Pharmacology and Toxicology , School of Pharmacy, Ardabil University of Medical Science , Ardabil , Iran ; Students Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors: Ahmad
authors: A
authors: Salimi
authors: b Iranian Blood Transfusion Organization , Tehran , Iran.
authors: Mehryar Habibi
authors: MH
authors: Roudkenar
authors: c Emam Hosein Educational Hospital, Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors: Leila
authors: L
authors: Sadeghi
authors: d Department of Laboratory Sciences , Faculty of Paramedicine, Mazandaran University of Medical Sciences , Sari , Iran.
authors: Alireza
authors: A
authors: Mohseni
authors: e Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors: Enayatollah
authors: E
authors: Seydi
authors: e Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences , Tehran , Iran.
authors: Nahal
authors: N
authors: Pirahmadi
authors: e Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences , Tehran , Iran.|f SBMU Pharmaceutical Sciences Research Center , Tehran , Iran.
authors: Jalal
authors: J
authors: Pourahmad
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D016513:Mice, SCID; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047309:Flavones; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D020782:Matrix Metalloproteinases; C023717:acacetin