title: Antiproliferative activity of the isoindigo 5'-Br in HL-60 cells is mediated by apoptosis, dysregulation of mitochondrial functions and arresting cell cycle at G0/G1 phase.
abstract: Our new compound, 5'-Br [(E)-1-(5'-bromo-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f]quinoline-8-carboxylic acid], had shown strong, selective antiproliferative activity against different cancer cell lines. Here, we aim to comprehensively characterize the mechanisms associated with its cytotoxicity in the human promyelocytic leukemia HL-60 cells. We focused at studying the involvement of apoptotic pathway and cell cycle effects. 5'-Br significantly inhibited proliferation by inducing caspase-dependent apoptosis. Involvement of caspase independent mechanism is also possible due to observed inability of z-VAD-FMK to rescue apoptotic cells. 5'-Br was found to trigger intrinsic apoptotic pathway as indicated by depolarization of the mitochondrial inner membrane, decreased level of cellular ATP, modulated expression and phosphorylation of Bcl-2 leading to loss of its association with Bax, and increased release of cytochrome c. 5'-Br treated cells were found arrested at G0/G1 phase with modulation in protein levels of cyclins, dependent kinases and their inhibitors. Expression and enzymatic activity of CDK2 and CDK4 was found inhibited. Retinoblastoma protein (Rb) phosphorylation was also inhibited whereas p21 protein levels were increased. These results suggest that the antiproliferative mechanisms of action of 5'-Br could involve apoptotic pathways, dysregulation of mitochondrial functions and disruption of cell cycle checkpoint.
authors: Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), National Guard Health Affairs, P.O. Box: 3660, Mail Code: 3127, Riyadh 11481, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia. Electronic address: salehay@ksau-hs.edu.sa.
authors: Ayman M
authors: AM
authors: Saleh
authors: Department of Chemistry, Faculty of Science, The University of Jordan, Amman 11942, Jordan.
authors: Mustafa M
authors: MM
authors: El-Abadelah
authors: King Abdullah International Medical Research Center (KAIMRC), National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
authors: Mohammad Azhar
authors: MA
authors: Aziz
authors: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan.
authors: Mutasem O
authors: MO
authors: Taha
authors: Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), National Guard Health Affairs, P.O. Box: 3660, Mail Code: 3127, Riyadh 11481, Saudi Arabia; Department of Microbiology, Faculty of Sciences and Technology, Al-Neelain University, Khartoum, Sudan.
authors: Amre
authors: A
authors: Nasr
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University (NSU), Fort Lauderdale, Florida 33328, USA.
authors: Syed A A
authors: SA
authors: Rizvi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*
chemical_list: D007211:Indoles; C049010:isoindigotin
keywords: Anticancer; Apoptosis; CDK; Cell cycle; Isoindigo; Mitochondria dysfunction